Molecules

2024

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28 pages, 10685 KiB

Open AccessArticle

Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells

by Zhuo Zhang, Qianqian Shen, Yiyi Ji, Yanjie Ma, Haiyang Hou, Huajie Yang, Yinjie Zhu, Yi Chen and Youhong Hu

Molecules 2024, 29(18), 4503; https://doi.org/10.3390/molecules29184503 - 23 Sep 2024

Viewed by 868

Abstract

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, [...] Read more.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure–activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC₅₀ value of 0.47 μM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study. Full article

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2023

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19 pages, 659 KiB

Open AccessReview

Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects

by Bimala Dhakal, Yoko Tomita, Paul Drew, Timothy Price, Guy Maddern, Eric Smith and Kevin Fenix

Molecules 2023, 28(8), 3624; https://doi.org/10.3390/molecules28083624 - 21 Apr 2023

Cited by 9 | Viewed by 2985

Abstract

Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal [...] Read more.

Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics. Full article

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15 pages, 3286 KiB

Open AccessArticle

LncRNA JHDM1D-AS1 Is a Key Biomarker for Progression and Modulation of Gemcitabine Sensitivity in Bladder Cancer Cells

by Isadora Oliveira Ansaloni Pereira, Glenda Nicioli da Silva, Tamires Cunha Almeida, Ana Paula Braga Lima, André Luiz Ventura Sávio, Katia Ramos Moreira Leite and Daisy Maria Fávero Salvadori

Molecules 2023, 28(5), 2412; https://doi.org/10.3390/molecules28052412 - 6 Mar 2023

Cited by 2 | Viewed by 2200

Abstract

Long non-coding RNAs are frequently found to be dysregulated and are linked to carcinogenesis, aggressiveness, and chemoresistance in a variety of tumors. As expression levels of the JHDM1D gene and lncRNA JHDM1D-AS1 are altered in bladder tumors, we sought to use their combined [...] Read more.

Long non-coding RNAs are frequently found to be dysregulated and are linked to carcinogenesis, aggressiveness, and chemoresistance in a variety of tumors. As expression levels of the JHDM1D gene and lncRNA JHDM1D-AS1 are altered in bladder tumors, we sought to use their combined expression to distinguish between low-and high-grade bladder tumors by RTq-PCR. In addition, we evaluated the functional role of JHDM1D-AS1 and its association with the modulation of gemcitabine sensitivity in high-grade bladder-tumor cells. J82 and UM-UC-3 cells were treated with siRNA-JHDM1D-AS1 and/or three concentrations of gemcitabine (0.39, 0.78, and 1.56 µM), and then submitted to cytotoxicity testing (XTT), clonogenic survival, cell cycle progression, cell morphology, and cell migration assays. When JHDM1D and JHDM1D-AS1 expression levels were used in combination, our findings indicated favorable prognostic value. Furthermore, the combined treatment resulted in greater cytotoxicity, a decrease in clone formation, G0/G1 cell cycle arrest, morphological alterations, and a reduction in cell migration capacity in both lineages compared to the treatments alone. Thus, silencing of JHDM1D-AS1 reduced the growth and proliferation of high-grade bladder-tumor cells and increased their sensitivity to gemcitabine treatment. In addition, the expression of JHDM1D/JHDM1D-AS1 indicated potential prognostic value in the progression of bladder tumors. Full article

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15 pages, 1326 KiB

Open AccessReview

Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors

by Shahnaz D. Vellani, Anthony Nigro, Shangari Varatharajan, Lance D. Dworkin and Justin Fortune Creeden

Molecules 2023, 28(5), 2047; https://doi.org/10.3390/molecules28052047 - 22 Feb 2023

Cited by 2 | Viewed by 2313

Abstract

Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have [...] Read more.

Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here. Full article

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16 pages, 3741 KiB

Open AccessReview

The Functional Roles of ISG15/ISGylation in Cancer

by Yin Yuan, Hai Qin, Huilong Li, Wanjin Shi, Lichen Bao, Shengtao Xu, Jun Yin and Lufeng Zheng

Molecules 2023, 28(3), 1337; https://doi.org/10.3390/molecules28031337 - 31 Jan 2023

Cited by 10 | Viewed by 4743

Abstract

The protein ISG15 encoded by interferon-stimulated gene (ISG) 15 is the first identified member of the ubiquitin-like protein family and exists in the form of monomers and conjugated complexes. Like ubiquitin, ISG15 can mediate an ubiquitin-like modification by covalently modifying other proteins, known [...] Read more.

The protein ISG15 encoded by interferon-stimulated gene (ISG) 15 is the first identified member of the ubiquitin-like protein family and exists in the form of monomers and conjugated complexes. Like ubiquitin, ISG15 can mediate an ubiquitin-like modification by covalently modifying other proteins, known as ISGylation. There is growing evidence showing that both the free and conjugated ISG15 are involved in multiple key cellular processes, including autophagy, exosome secretion, DNA repair, immune regulation, and cancer occurrence and progression. In this review, we aim to further clarify the function of ISG15 and ISGylation in cancer, demonstrate the important relationship between ISG15/ISGylation and cancer, and emphasize new insights into the different roles of ISG15/ISGylation in cancer progression. This review may contribute to therapeutic intervention in cancer. However, due to the limitations of current research, the regulation of ISG15/ISGylation on cancer progression is not completely clear, thus further comprehensive and sufficient correlation studies are still needed. Full article

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2021

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28 pages, 4686 KiB

Open AccessArticle

Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes

by Badriah Saad Al-Farhan, Maram T. Basha, Laila H. Abdel Rahman, Ahmed M. M. El-Saghier, Doaa Abou El-Ezz, Adel A. Marzouk, Mohamed R. Shehata and Ehab M. Abdalla

Molecules 2021, 26(16), 4725; https://doi.org/10.3390/molecules26164725 - 4 Aug 2021

Cited by 38 | Viewed by 3973

Abstract

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2′-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), [...] Read more.

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2′-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, ¹H NMR, ¹³C NMR, UV–VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H₂O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H₂O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC₅₀ values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC₅₀ values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature. Full article

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22 pages, 9575 KiB

Open AccessReview

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention

by Layan Dahabra, Grace Broadberry, Adam Le Gresley, Mohammad Najlah and Mouhamad Khoder

Molecules 2021, 26(6), 1698; https://doi.org/10.3390/molecules26061698 - 18 Mar 2021

Cited by 21 | Viewed by 5998

Abstract

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, [...] Read more.

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention. Full article

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15 pages, 3116 KiB

Open AccessArticle

The Antiproliferative and Apoptotic Effect of a Novel Synthesized S-Triazine Dipeptide Series, and Toxicity Screening in Zebrafish Embryos

by Azizah M. Malebari, Rakia Abd Alhameed, Zainab Almarhoon, Muhammad Farooq, Mohammad A. M. Wadaan, Anamika Sharma, Beatriz G. de la Torre, Fernando Albericio and Ayman El-Faham

Molecules 2021, 26(4), 1170; https://doi.org/10.3390/molecules26041170 - 22 Feb 2021

Cited by 7 | Viewed by 2808

Abstract

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and [...] Read more.

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a—which contains morpholine, aniline, and glycylglycinate methyl ester—showed a high level of cytotoxicity against MCF-7 cells with IC₅₀ values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer. Full article

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23 pages, 2269 KiB

Open AccessArticle

Marine Exopolysaccharide Complexed With Scandium Aimed as Theranostic Agents

by Mattia Mazza, Cyrille Alliot, Corinne Sinquin, Sylvia Colliec-Jouault, Pascal E. Reiller and Sandrine Huclier-Markai

Molecules 2021, 26(4), 1143; https://doi.org/10.3390/molecules26041143 - 20 Feb 2021

Cited by 6 | Viewed by 2706

Abstract

(1) Background: Exopolysaccharide (EPS) derivatives, produced by Alteromonas infernus bacterium, showed anti-metastatic properties. They may represent a new class of ligands to be combined with theranostic radionuclides, such as ⁴⁷Sc/⁴⁴Sc. The goal of this work was to investigate the feasibility [...] Read more.

(1) Background: Exopolysaccharide (EPS) derivatives, produced by Alteromonas infernus bacterium, showed anti-metastatic properties. They may represent a new class of ligands to be combined with theranostic radionuclides, such as ⁴⁷Sc/⁴⁴Sc. The goal of this work was to investigate the feasibility of such coupling. (2) Methods: EPSs, as well as heparin used as a drug reference, were characterized in terms of molar mass and dispersity using Asymmetrical Flow Field-Flow Fractionation coupled to Multi-Angle Light Scattering (AF4-MALS). The intrinsic viscosity of EPSs at different ionic strengths were measured in order to establish the conformation. To determine the stability constants of Sc with EPS and heparin, a Free-ion selective radiotracer extraction (FISRE) method has been used. (3) Results: AF4-MALS showed that radical depolymerization produces monodisperse EPSs, suitable for therapeutic use. EPS conformation exhibited a lower hydrodynamic volume for the highest ionic strengths. The resulting random-coiled conformation could affect the complexation with metal for high concentration. The LogK of Sc-EPS complexes have been determined and showing that they are comparable to the Sc-Hep. (4) Conclusions: EPSs are very promising to be coupled with the theranostic pair of scandium for Nuclear Medicine. Full article

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2020

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29 pages, 7046 KiB

Open AccessArticle

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

by Majd S. Hijjawi, Reem Fawaz Abutayeh and Mutasem O. Taha

Molecules 2020, 25(24), 6003; https://doi.org/10.3390/molecules25246003 - 18 Dec 2020

Cited by 13 | Viewed by 3478

Abstract

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug [...] Read more.

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC₅₀ values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC₅₀ on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules. Full article

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20 pages, 2847 KiB

Open AccessArticle

Synthesis, In Silico and In Vitro Assessment of New Quinazolinones as Anticancer Agents via Potential AKT Inhibition

by Ahmed A. Noser, Mohamed El-Naggar, Thoria Donia and Aboubakr H. Abdelmonsef

Molecules 2020, 25(20), 4780; https://doi.org/10.3390/molecules25204780 - 18 Oct 2020

Cited by 32 | Viewed by 4395

Abstract

A series of novel quinazolinone derivatives (2–13) was synthesized and examined for their cytotoxicity to HepG2, MCF-7, and Caco-2 in an MTT assay. Among these derivatives, compounds 4 and 9 exhibited significant cytotoxic activity against Caco-2, HepG2, and MCF-7 [...] Read more.

A series of novel quinazolinone derivatives (2–13) was synthesized and examined for their cytotoxicity to HepG2, MCF-7, and Caco-2 in an MTT assay. Among these derivatives, compounds 4 and 9 exhibited significant cytotoxic activity against Caco-2, HepG2, and MCF-7 cancer cells. Compound 4 had more significant inhibitory effects than compound 9 on Caco-2, HepG2, and MCF-7 cell lines, with IC₅₀ values of 23.31 ± 0.09, 53.29 ± 0.25, and 72.22 ± 0.14µM, respectively. The AKT pathway is one of human cancer’s most often deregulated signals. AKT is also overexpressed in human cancers such as glioma, lung, breast, ovarian, gastric, and pancreas. A molecular docking study was performed to analyze the inhibitory action of newly synthetic quinazolinone derivatives against Homo sapiens AKT1 protein. Molecular docking simulations were found to be in accordance with in vitro studies, and hence supported the biological activity. The results suggested that compounds 4 and 9 could be used as drug candidates for cancer therapy via its potential inhibition of AKT1 as described by docking study. Full article

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13 pages, 1975 KiB

Open AccessArticle

Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

by Eun Yeong Lim, Joon Park, Yun Tai Kim and Min Jung Kim

Molecules 2020, 25(20), 4619; https://doi.org/10.3390/molecules25204619 - 11 Oct 2020

Cited by 18 | Viewed by 4500

Abstract

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. [...] Read more.

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). Full article

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20 pages, 5833 KiB

Open AccessArticle

Synthesis and Cytotoxic Activity of Novel C-23-Modified Asiatic Acid Derivatives

by Yi-hong Lu, Ming-cang Chen, Fang Liu, Zhou Xu, Xiao-ting Tian, Yang Xie and Cheng-gang Huang

Molecules 2020, 25(16), 3709; https://doi.org/10.3390/molecules25163709 - 14 Aug 2020

Cited by 5 | Viewed by 2799

Abstract

We selectively oxidized the C-23 hydroxyl group in an asiatic acid (AA) derivative and then, for the first time with AA, modification of the C-23 carboxyl group was conducted to synthesize a series of new AA derivatives. The evaluation of their cytotoxic activities [...] Read more.

We selectively oxidized the C-23 hydroxyl group in an asiatic acid (AA) derivative and then, for the first time with AA, modification of the C-23 carboxyl group was conducted to synthesize a series of new AA derivatives. The evaluation of their cytotoxic activities against two human cancer cell lines (SKOV-3 and HCT116) using the MTT assay in vitro revealed a distinctive structure activity relationship (SAR) associated with the intramolecular hydrogen bonding of the amide moiety at C-23. According to the established SAR, the cytotoxic activities of four promising compounds were then evaluated against MCF-7, A549, A2780, HepG2 and HL-60 cancer cell lines. Compound 10 had the best cytotoxic activity among all tested derivatives in the HL-60 cell line, giving IC₅₀ = 0.47 μM, while showing no cytotoxic effect against human normal cells (HUVEC). Full article

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2019

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16 pages, 4727 KiB

Open AccessArticle

Design, Synthesis and Preliminary Biological Evaluation of Benzylsulfone Coumarin Derivatives as Anti-Cancer Agents

by Tao Wang, Tao Peng, Xiaoxue Wen, Gang Wang, Yunbo Sun, Shuchen Liu, Shouguo Zhang and Lin Wang

Molecules 2019, 24(22), 4034; https://doi.org/10.3390/molecules24224034 - 7 Nov 2019

Cited by 21 | Viewed by 4046

Abstract

In this work, a series of benzylsulfone coumarin derivatives 5a–5o were synthesized and characterized. Kinase inhibitory activity assay indicated that most of the compounds showed considerable activity against PI3K. Anti-tumor activity studies of the active compounds were also carried out in [...] Read more.

In this work, a series of benzylsulfone coumarin derivatives 5a–5o were synthesized and characterized. Kinase inhibitory activity assay indicated that most of the compounds showed considerable activity against PI3K. Anti-tumor activity studies of the active compounds were also carried out in vitro on the Hela, HepG2, H1299, HCT-116, and MCF-7 tumor cell lines by MTS assay. The structure–activity relationships (SARs) of these compounds were analyzed in detail. Compound 5h exhibited the most potent activities against the mentioned cell lines with IC₅₀ values ranging from 18.12 to 32.60 μM, followed by 5m with IC₅₀ values of 29.30–42.14 μM. Furthermore, 5h and 5m clearly retarded the migration of Hela cells in vitro. Next, an in silico molecular docking study was conducted to evaluate the binding models of 5h and 5m towards PI3Kα and PI3Kβ. Collectively, the above findings suggested that compounds 5h and 5m might be promising PI3K inhibitors deserving further investigation for cancer treatment. Full article

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22 pages, 3467 KiB

Open AccessArticle

Benzoxaboroles—Novel Autotaxin Inhibitors

by Kristina Kraljić, Dubravko Jelić, Dinko Žiher, Adam Cvrtila, Snježana Dragojević, Verona Sinković and Milan Mesić

Molecules 2019, 24(19), 3419; https://doi.org/10.3390/molecules24193419 - 20 Sep 2019

Cited by 19 | Viewed by 5002

Abstract

Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last [...] Read more.

Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability). Full article

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13 pages, 4878 KiB

Open AccessArticle

Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration

by Soyoung Hwang, Dong Min Shin and Jeong Hee Hong

Molecules 2019, 24(18), 3409; https://doi.org/10.3390/molecules24183409 - 19 Sep 2019

Cited by 18 | Viewed by 3814

Abstract

Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and [...] Read more.

Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na⁺-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent. Full article

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19 pages, 664 KiB

Open AccessCommunication

Design and Synthesis of Benzimidazole-Chalcone Derivatives as Potential Anticancer Agents

by Cheng-Ying Hsieh, Pi-Wen Ko, Yu-Jui Chang, Mohit Kapoor, Yu-Chuan Liang, Hsueh-Liang Chu, Hui-Hsien Lin, Jia-Cherng Horng and Ming-Hua Hsu

Molecules 2019, 24(18), 3259; https://doi.org/10.3390/molecules24183259 - 6 Sep 2019

Cited by 70 | Viewed by 7287

Abstract

Numerous reports have shown that conjugated benzimidazole derivatives possess various kinds of biological activities, including anticancer properties. In this report, we designed and synthesized 24 new molecules comprising a benzimidazole ring, arene, and alkyl chain-bearing cyclic moieties. The results showed that the N [...] Read more.

Numerous reports have shown that conjugated benzimidazole derivatives possess various kinds of biological activities, including anticancer properties. In this report, we designed and synthesized 24 new molecules comprising a benzimidazole ring, arene, and alkyl chain-bearing cyclic moieties. The results showed that the N-substituted benzimidazole derivatives bearing an alkyl chain and a nitrogen-containing 5- or 6-membered ring enhanced the cytotoxic effects on human breast adenocarcinoma (MCF-7) and human ovarian carcinoma (OVCAR-3) cell lines. Among the 24 synthesized compounds, (2E)-1-(1-(3-morpholinopropyl)-1H-benzimidazol-2 -yl)-3-phenyl-2-propen-1-one) (23a) reduced the proliferation of MCF-7 and OVCAR-3 cell lines demonstrating superior outcomes to those of cisplatin. Full article

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16 pages, 5768 KiB

Open AccessArticle

Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents

by Niu-niu Zhang, Bai-jiao An, Yan Zhou, Xing-shu Li and Ming Yan

Molecules 2019, 24(6), 1173; https://doi.org/10.3390/molecules24061173 - 25 Mar 2019

Cited by 5 | Viewed by 5806

Abstract

Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side [...] Read more.

Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound 31e exhibited potent antiproliferative activity (IC₅₀ (50% inhibitory concentration) = 0.026 μΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells. A mechanism study demonstrated that 31e induced G1 phase (First growth phase or G indicating gap) arrest, inhibited the phosphorylation of c-Met and its downstream signaling component, Akt (Protein Kinase B), and also inhibited the migration of hepatic carcinoma 97H cells. Full article

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21 pages, 4107 KiB

Open AccessArticle

Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents

by Mohamed El-Naggar, Hanan A. Sallam, Safaa S. Shaban, Salwa S. Abdel-Wahab, Abd El-Galil E. Amr, Mohammad E. Azab, Eman S. Nossier and Mohamed A. Al-Omar

Molecules 2019, 24(6), 1066; https://doi.org/10.3390/molecules24061066 - 18 Mar 2019

Cited by 48 | Viewed by 5962

Abstract

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic [...] Read more.

A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 proved to be the most active DHFR inhibitors with an IC₅₀ range of 0.04 ± 0.82–1.00 ± 0.85 µM, in comparison with Methotrexate (IC₅₀ = 0.14 ± 1.38 µM). The highly potent DHFR inhibitors shared a similar molecular docking mode and made a critical hydrogen bond and arene‒arene interactions via Ser59 and Phe31 amino acid residues, respectively. Full article

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15 pages, 3503 KiB

Open AccessArticle

The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro

by Melanie J. Predebon, Danielle R. Bond, Joshua Brzozowski, Helen Jankowski, Fiona Deane, Mark Tarleton, Aron A. Shaw, Adam McCluskey, Michael C. Bowyer, Judith Weidenhofer and Christopher J. Scarlett

Molecules 2019, 24(3), 524; https://doi.org/10.3390/molecules24030524 - 31 Jan 2019

Cited by 7 | Viewed by 4443

Abstract

Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The [...] Read more.

Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM–100 µM) on all three cell lines, with IC₅₀ values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials. Full article

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18 pages, 2208 KiB

Open AccessArticle

Design, Synthesis, Anticancer Evaluation and Molecular Modeling of Novel Estrogen Derivatives

by Abd El-Galil E. Amr, Elsayed A. Elsayed, Mohamed A. Al-Omar, Hanan O. Badr Eldin, Eman S. Nossier and Mohamed M. Abdallah

Molecules 2019, 24(3), 416; https://doi.org/10.3390/molecules24030416 - 24 Jan 2019

Cited by 34 | Viewed by 4786

Abstract

A series of estrone derivatives 3–8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and [...] Read more.

A series of estrone derivatives 3–8 was designed and synthesized using estrone arylmethylenes 2a,b as starting materials and their structures were confirmed by different spectral data and elemental analyses. All the newly synthesized compounds exhibited potent in vitro and in vivo cytotoxic activities against breast cancer cell lines. In addition, all compounds were subjected to in vitro and in vivo inhibition assays for EGFR and VEGFR-2 kinases as well as p53 ubiquitination activity to obtain more details about their mechanism of action. Based on the promising results, a molecular docking study was investigated for the most representative compound 5a against the two targets, EGFR and VEGFR-2 kinases, to assess its binding affinity, hoping to rationalize and obtain potent anticancer agents in the future. Full article

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2018

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18 pages, 2707 KiB

Open AccessArticle

Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors

by Abd El-Galil E. Amr, Mohamed H. Abo-Ghalia, Gaber O. Moustafa, Mohamed A. Al-Omar, Eman S. Nossier and Elsayed A. Elsayed

Molecules 2018, 23(10), 2416; https://doi.org/10.3390/molecules23102416 - 20 Sep 2018

Cited by 60 | Viewed by 5015

Abstract

A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, ¹H and ¹³C-NMR, and MS spectral data and [...] Read more.

A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, ¹H and ¹³C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC₅₀ values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases. Full article

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19 pages, 2680 KiB

Open AccessArticle

Synthesis, Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors

by Göknil Pelin Coşkun, Teodora Djikic, Taha Bartu Hayal, Nezaket Türkel, Kemal Yelekçi, Fikrettin Şahin and Ş. Güniz Küçükgüzel

Molecules 2018, 23(8), 1969; https://doi.org/10.3390/molecules23081969 - 6 Aug 2018

Cited by 24 | Viewed by 6148

Abstract

Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating [...] Read more.

Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results. Full article

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14 pages, 25666 KiB

Open AccessArticle

Identification by Molecular Docking of Homoisoflavones from Leopoldia comosa as Ligands of Estrogen Receptors

by Fedora Grande, Bruno Rizzuti, Maria A. Occhiuzzi, Giuseppina Ioele, Teresa Casacchia, Fabrizio Gelmini, Rita Guzzi, Antonio Garofalo and Giancarlo Statti

Molecules 2018, 23(4), 894; https://doi.org/10.3390/molecules23040894 - 12 Apr 2018

Cited by 58 | Viewed by 6800

Abstract

The physiological responses to estrogen hormones are mediated within specific tissues by at least two distinct receptors, ERα and ERβ. Several natural and synthetic molecules show activity by interacting with these proteins. In particular, a number of vegetal compounds known as phytoestrogens shows [...] Read more.

The physiological responses to estrogen hormones are mediated within specific tissues by at least two distinct receptors, ERα and ERβ. Several natural and synthetic molecules show activity by interacting with these proteins. In particular, a number of vegetal compounds known as phytoestrogens shows estrogenic or anti-estrogenic activity. The majority of these compounds belongs to the isoflavones family and the most representative one, genistein, shows anti-proliferative effects on various hormone-sensitive cancer cells, including breast, ovarian and prostate cancer. In this work we describe the identification of structurally related homoisoflavones isolated from Leopoldia comosa (L.) Parl. (L. comosa), a perennial bulbous plant, potentially useful as hormonal substitutes or complements in cancer treatments. Two of these compounds have been selected as potential ligands of estrogen receptors (ERs) and the interaction with both isoforms of estrogen receptors have been investigated through molecular docking on their crystallographic structures. The results provide evidence of the binding of these compounds to the target receptors and their interactions with key residues of the active sites of the two proteins, and thus they could represent suitable leads for the development of novel tools for the dissection of ER signaling and the development of new pharmacological treatments in hormone-sensitive cancers. Full article

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24 pages, 32541 KiB

Open AccessReview

Polymer-Mediated Delivery of siRNAs to Hepatocellular Carcinoma: Variables Affecting Specificity and Effectiveness

by Rossella Farra, Francesco Musiani, Francesca Perrone, Maja Čemažar, Urška Kamenšek, Federica Tonon, Michela Abrami, Aleš Ručigaj, Mario Grassi, Gabriele Pozzato, Deborah Bonazza, Fabrizio Zanconati, Giancarlo Forte, Maguie El Boustani, Lucia Scarabel, Marica Garziera, Concetta Russo Spena, Lucia De Stefano, Barbara Salis, Giuseppe Toffoli, Flavio Rizzolio, Gabriele Grassi and Barbara Dapas Show full author list Hide full author list

Molecules 2018, 23(4), 777; https://doi.org/10.3390/molecules23040777 - 28 Mar 2018

Cited by 16 | Viewed by 7078

Abstract

Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules [...] Read more.

Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD) and particularly small interfering RNAs (siRNAs), are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC), a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work. Full article

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21 pages, 931 KiB

Open AccessReview

Antitumour, Antimicrobial, Antioxidant and Antiacetylcholinesterase Effect of Ganoderma Lucidum Terpenoids and Polysaccharides: A Review

by Darija Cör, Željko Knez and Maša Knez Hrnčič

Molecules 2018, 23(3), 649; https://doi.org/10.3390/molecules23030649 - 13 Mar 2018

Cited by 298 | Viewed by 29587

Abstract

Ganoderma lucidum (Reishi) is a popular medicinal mushroom and has been used in oriental medicine because of its promoting effects on health and life expectancy. G. lucidum contains various compounds with a high grade of biological activty, which increase the immunity and show [...] Read more.

Ganoderma lucidum (Reishi) is a popular medicinal mushroom and has been used in oriental medicine because of its promoting effects on health and life expectancy. G. lucidum contains various compounds with a high grade of biological activty, which increase the immunity and show antitumour, antimicrobial, anti-inflammatory, antioxidant and acetylcholinesterase inhibitory activity. Several of these substances belong to the triterpenoids and polysaccharides classes. Proteins, lipids, phenols, sterols, etc. are also present. In the present review, an extensive overview of the presence of antitumour, antimicrobial, antioxidant and antiacetylcholinesterase compounds in G. lucidum extracts will be given, along with an evaluation of their therapeutic effects. Full article

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16 pages, 2238 KiB

Open AccessArticle

Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand

by Pavel Štarha, Zdeněk Trávníček, Ján Vančo and Zdeněk Dvořák

Molecules 2018, 23(2), 420; https://doi.org/10.3390/molecules23020420 - 14 Feb 2018

Cited by 21 | Viewed by 4842

Abstract

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶-pcym)(bphen)(dca)]PF₆ (Ru-dca) and [Os(η⁶-pcym)(bphen)(dca)]PF₆ (Os-dca) containing dichloroacetate(1–) (dca) as the releasable O-donor [...] Read more.

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶-pcym)(bphen)(dca)]PF₆ (Ru-dca) and [Os(η⁶-pcym)(bphen)(dca)]PF₆ (Os-dca) containing dichloroacetate(1–) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by ¹H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC₅₀ = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC₅₀ = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC₅₀ = 19.1 μM for Ru-dca and IC₅₀ = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes. Full article

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2017

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1803 KiB

Open AccessArticle

Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects

by Mohamed Alswah, Ashraf H. Bayoumi, Kamal Elgamal, Ahmed Elmorsy, Saleh Ihmaid and Hany E. A. Ahmed

Molecules 2018, 23(1), 48; https://doi.org/10.3390/molecules23010048 - 27 Dec 2017

Cited by 85 | Viewed by 7593

Abstract

A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed [...] Read more.

A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC₅₀ values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets. Full article

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Open AccessArticle

rLj-RGD3 Suppresses the Growth of HeyA8 Cells in Nude Mice

by Yuanyuan Zheng, Li Lv, Longda Yi, Rui Wu, Rong Xiao and Jihong Wang

Molecules 2017, 22(12), 2234; https://doi.org/10.3390/molecules22122234 - 15 Dec 2017

Cited by 6 | Viewed by 4889

Abstract

In the previous study, rLj-RGD3, a recombinant toxin protein which contains three RGD motifs, was reported to not only inhibit the proliferation of an ovarian cancer cell line, HeyA8 cells, by inducing apoptosis, but also block their adhesion, migration and invasion processes. However, [...] Read more.

In the previous study, rLj-RGD3, a recombinant toxin protein which contains three RGD motifs, was reported to not only inhibit the proliferation of an ovarian cancer cell line, HeyA8 cells, by inducing apoptosis, but also block their adhesion, migration and invasion processes. However, whether rLj-RGD3 could also suppress the tumor growth in HeyA8 xenografted mice has not been reported yet. In the present study, rLj-RGD3 was intraperitoneally injected in the nude mice bearing HeyA8 tumors. Compared with the control group (normal saline), rLj-RGD3 inhibited the tumor growth significantly in the HeyA8 xenografted mice in a dose-dependent manner without affecting their body weights. Based on the H&E, Hoechst 33258 and TUNEL staining assays, as well as western blot analysis, rLj-RGD3 reduced the weight and volume of the solid tumors, probably by disturbing the tissue structure, inducing apoptosis and suppressing the FAK/PI3K/AKT pathway. Most importantly, rLj-RGD3 was found to prolong the survival days of the ovarian tumor xenografted mice, which suggested rLj-RGD3 might act as an effective and safe drug to treat ovarian cancer patients. Full article

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Open AccessArticle

Synthesis and In Vitro Antiproliferative Activity of 11-Substituted Neocryptolepines with a Branched ω-Aminoalkylamino Chain

by Elkhabiry Shaban, Marta Świtalska, Li Wang, Ning Wang, Fan Xiu, Ikuya Hayashi, Tran Anh Ngoc, Sachie Nagae, Samah El-Ghlban, Shiho Shimoda, Ahmed Abdel Aleem El Gokha, Ibrahim El Tantawy El Sayed, Joanna Wietrzyk and Tsutomu Inokuchi

Molecules 2017, 22(11), 1954; https://doi.org/10.3390/molecules22111954 - 12 Nov 2017

Cited by 9 | Viewed by 4623

Abstract

Neocryptolepine, which is a kind of tetracyclic indoloquinoline alkaloid, exhibits the inhibition of topoisomerase II and shows antiproliferative activity. The present study describes the synthesis and antiproliferative evaluation of several neocryptolepine analogues carrying a branched, functionalized dibasic side chain at C11. These 2-substituted [...] Read more.

Neocryptolepine, which is a kind of tetracyclic indoloquinoline alkaloid, exhibits the inhibition of topoisomerase II and shows antiproliferative activity. The present study describes the synthesis and antiproliferative evaluation of several neocryptolepine analogues carrying a branched, functionalized dibasic side chain at C11. These 2-substituted 5-methyl-indolo[2,3-b]quinoline derivatives were prepared by nucleophilic aromatic substitution (S_NAr) of 11-chloroneocryptolepines with appropriate 1,2- and 1,3-diamines. Some of the 11-(ω-aminoalkylamino) derivatives were further transformed into 11-ureido and thioureido analogues. Many of the prepared neocryptolepine derivatives showed submicromolar antiproliferative activity against the human leukemia MV4-11 cell line. Among them, 11-(3-amino-2-hydroxy)propylamino derivatives 2h and 2k were the most cytotoxic with a mean IC₅₀ value of 0.042 μM and 0.057 μM against the MV4-11 cell line, 0.197 μM and 0.1988 μM against the A549 cell line, and 0.138 μM and 0.117 μM against the BALB/3T3 cell line, respectively. Full article

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Open AccessArticle

Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety

by Hong Chen, Bing-Bing Xu, Tao Sun, Zhan Zhou, Hui-Yuan Ya and Mu Yuan

Molecules 2017, 22(11), 1857; https://doi.org/10.3390/molecules22111857 - 29 Oct 2017

Cited by 13 | Viewed by 4659

Abstract

Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer [...] Read more.

Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC₅₀) < 2 μM). The structure–activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data. This work provides a potential lead compound for anticancer agent development focusing on prostate cancer therapy. Full article

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Open AccessArticle

Berberine Activates Aryl Hydrocarbon Receptor but Suppresses CYP1A1 Induction through miR-21-3p Stimulation in MCF-7 Breast Cancer Cells

by Sheng-Nan Lo, Chun-Wei Wang, Yueh-Shieh Chen, Chiung-Chiao Huang, Tian-Shung Wu, Lih-Ann Li, I-Jung Lee and Yune-Fang Ueng

Molecules 2017, 22(11), 1847; https://doi.org/10.3390/molecules22111847 - 28 Oct 2017

Cited by 29 | Viewed by 6254

Abstract

Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR) activation and cytochrome P450 (CYP) 1 in the estrogen receptor (ER)α(+) [...] Read more.

Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR) activation and cytochrome P450 (CYP) 1 in the estrogen receptor (ER)α(+) MCF-7 breast cancer cells. Among protoberberines at non-cytotoxic concentrations (≤10 μM), berberine had the most potent and statistically significant effects on AhR activation and CYP1A1/1A2/1B1 mRNA induction. The 24-h exposure to 10 μM berberine did not change CYP1A1 mRNA stability, protein level and function. Berberine significantly increased micro RNA (miR)-21-3p by 36% and the transfection of an inhibitor of miR-21-3p restored the induction of CYP1A1 protein with a 50% increase. These findings demonstrate that the ring opening of the methylenedioxyl moiety in berberine decreased AhR activation in MCF-7 cells. While CYP1A1 mRNA was elevated, berberine-induced miR-21-3p suppressed the increase of functional CYP1A1 protein expression. Full article

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Open AccessArticle

Studies on the Synthesis, Photophysical and Biological Evaluation of Some Unsymmetrical Meso-Tetrasubstituted Phenyl Porphyrins

by Rica Boscencu, Gina Manda, Natalia Radulea, Radu Petre Socoteanu, Laura Cristina Ceafalan, Ionela Victoria Neagoe, Isabel Ferreira Machado, Selma Huveyda Basaga and Luís Filipe Vieira Ferreira

Molecules 2017, 22(11), 1815; https://doi.org/10.3390/molecules22111815 - 25 Oct 2017

Cited by 20 | Viewed by 5355

Abstract

Abstract: We designed three unsymmetrical meso-tetrasubstituted phenyl porphyrins for further development as theranostic agents for cancer photodynamic therapy (PDT): 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (P2.2), Zn(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Zn(II)2.2) and Cu(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Cu(II)2.2). The porphyrinic compounds were synthesized and their structures were confirmed by elemental analysis, FT-IR, UV-Vis, EPR [...] Read more.

Abstract: We designed three unsymmetrical meso-tetrasubstituted phenyl porphyrins for further development as theranostic agents for cancer photodynamic therapy (PDT): 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (P2.2), Zn(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Zn(II)2.2) and Cu(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Cu(II)2.2). The porphyrinic compounds were synthesized and their structures were confirmed by elemental analysis, FT-IR, UV-Vis, EPR and NMR. The compounds had a good solubility in polar/nonpolar media. P2.2 and, to a lesser extent, Zn(II)2.2 were fluorescent, albeit with low fluoresence quantum yields. P2.2 and Zn(II)2.2 exhibited PDT-acceptable values of singlet oxygen generation. A “dark” cytotoxicity study was performed using cells that are relevant for the tumor niche (HT-29 colon carcinoma cells and L929 fibroblasts) and for blood (peripheral mononuclear cells). Cellular uptake of fluorescent compounds, cell viability/proliferation and death were evaluated. P2.2 was highlighted as a promising theranostic agent for PDT in solid tumors considering that P2.2 generated PDT-acceptable singlet oxygen yields, accumulated into tumor cells and less in blood cells, exhibited good fluorescence within cells for imagistic detection, and had no significant cytotoxicity in vitro against tumor and normal cells. Complexing of P2.2 with Zn(II) or Cu(II) altered several of its PDT-relevant properties. These are consistent arguments for further developing P2.2 in animal models of solid tumors for in vivo PDT. Full article

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Open AccessArticle

Pratol, an O-Methylated Flavone, Induces Melanogenesis in B16F10 Melanoma Cells via p-p38 and p-JNK Upregulation

by You Chul Chung, Seoyeon Kim, Jin Hwa Kim, Geun Soo Lee, Jung No Lee, Nam Ho Lee and Chang-Gu Hyun

Molecules 2017, 22(10), 1704; https://doi.org/10.3390/molecules22101704 - 11 Oct 2017

Cited by 32 | Viewed by 8060

Abstract

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis. It controls pigmentation in the skin. Activation of tyrosinase is currently the most common approach in the development of tanning and haircare products. Pratol is a 7-hydroxy-4-methoxyflavone found in Trifolium pratense. In this [...] Read more.

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis. It controls pigmentation in the skin. Activation of tyrosinase is currently the most common approach in the development of tanning and haircare products. Pratol is a 7-hydroxy-4-methoxyflavone found in Trifolium pratense. In this study, we investigated the effects of pratol on melanogenesis. We also studied the mechanism of action of pratol in B16F10 mouse melanoma cells. The cells were treated with various concentrations (6.25, 12.5, 25, and 50 μM) of pratol to observe its effects. The results showed that pratol significantly increased melanin content and tyrosinase activity in the cells without being cytotoxic. In addition, pratol strongly increased the expression of tyrosinase and tyrosinase-related protein-1 and 2 by enhancing the expression of microphthalmia-associated transcription factor. Furthermore, pratol stimulated melanogenesis via the phosphorylation of p38, c-Jun N-terminal kinases (JNK), and extracellular signal–regulated kinase (ERK). The findings from an assay searching for the inhibitor revealed that SB203580 (a specific p38 inhibitor) or SP600125 (a p-JNK inhibitor) attenuated pratol-induced cellular tyrosinase activity whereas PD98059 (an ERK inhibitor) did not. Additionally, pratol interfered with the phosphorylation of p-AKT. We also found that pratol-induced melanogenesis was reversed by H89, which is a specific protein kinase A inhibitor. The results suggest that, owing to its multi-functional properties, pratol may be a potential tanning agent or a therapeutic agent for hair depigmentation in the cosmetic industry. Full article

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Open AccessArticle

Inhibitory Effects of Total Triterpenoid Saponins Isolated from the Seeds of the Tea Plant (Camellia sinensis) on Human Ovarian Cancer Cells

by Ling-Yan Jia, Xue-Jin Wu, Ying Gao, Gary O. Rankin, Alexa Pigliacampi, Heather Bucur, Bo Li, You-Ying Tu and Yi Charlie Chen

Molecules 2017, 22(10), 1649; https://doi.org/10.3390/molecules22101649 - 30 Sep 2017

Cited by 29 | Viewed by 6908

Abstract

Ovarian cancer is regarded as one of the most severe malignancies for women in the world. Death rates have remained steady over the past five decades, due to the undeniable inefficiency of the current treatment in preventing its recurrence and death. The development [...] Read more.

Ovarian cancer is regarded as one of the most severe malignancies for women in the world. Death rates have remained steady over the past five decades, due to the undeniable inefficiency of the current treatment in preventing its recurrence and death. The development of new effective alternative agents for ovarian cancer treatment is becoming increasingly critical. Tea saponins (TS) are triterpenoidsaponins composed of sapogenins, glycosides, and organic acids, which possess a variety of pharmacological activities, and have shown promise in the anti-cancer field. Through cell CellTiter 96^® Aqueous One Solution Cell Proliferation assay (MTS) assay, colony formation, Hoechst 33342 staining assay, caspase-3/7 activities, flow cytometry for apoptosis analysis, and Western blot, we observed that TS isolated from the seeds of tea plants, Camellia sinensis, exhibited strong anti-proliferation inhibitory effects on OVCAR-3 and A2780/CP70 ovarian cancer cell lines. Our results indicate that TS may selectivity inhibit human ovarian cancer cells by mediating apoptosis through the extrinsic pathway, and initiating anti-angiogenesis via decreased VEGF protein levels in a HIF-1α-dependent pathway. Our data suggests that, in the future, TS could be incorporated into a potential therapeutic agent against human ovarian cancer. Full article

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Open AccessArticle

Anticarcinogenic Effect of Spices Due to Phenolic and Flavonoid Compounds—In Vitro Evaluation on Prostate Cells

by Zuzana Lackova, Hana Buchtelova, Zaneta Buchtova, Borivoj Klejdus, Zbynek Heger, Martin Brtnicky, Jindrich Kynicky, Ondrej Zitka and Vojtech Adam

Molecules 2017, 22(10), 1626; https://doi.org/10.3390/molecules22101626 - 28 Sep 2017

Cited by 11 | Viewed by 6849

Abstract

This study shows the effects of spices, and their phenolic and flavonoid compounds, on prostate cell lines (PNT1A, 22RV1 and PC3). The results of an MTT assay on extracts from eight spices revealed the strongest inhibitory effects were from black pepper and caraway [...] Read more.

This study shows the effects of spices, and their phenolic and flavonoid compounds, on prostate cell lines (PNT1A, 22RV1 and PC3). The results of an MTT assay on extracts from eight spices revealed the strongest inhibitory effects were from black pepper and caraway seed extracts. The strongest inhibitory effect on prostatic cells was observed after the application of extracts of spices in concentration of 12.5 mg·mL⁻¹. An LC/MS analysis identified that the most abundant phenolic and flavonoid compounds in black pepper are 3,4-dihydroxybenzaldehyde and naringenin chalcone, while the most abundant phenolic and flavonoid compounds in caraway seeds are neochlorogenic acid and apigenin. Using an MTT assay for the phenolic and flavonoid compounds from spices, we identified the IC₅₀ value of ~1 mmol·L⁻¹ PNT1A. The scratch test demonstrated that the most potent inhibitory effect on PNT1A, 22RV1 and PC3 cells is from the naringenin chalcone contained in black pepper. From the spectrum of compounds assessed, the naringenin chalcone contained in black pepper was identified as the most potent inhibitor of the growth of prostate cells. Full article

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Open AccessArticle

Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H⁺)-ATPase Inhibitors

by Renukadevi Patil, Arpita Kulshrestha, Anjali Tikoo, Sara Fleetwood, Gajendra Katara, Bala Kolli, William Seibel, Alice Gilman-Sachs, Shivaputra A. Patil and Kenneth D. Beaman

Molecules 2017, 22(9), 1559; https://doi.org/10.3390/molecules22091559 - 16 Sep 2017

Cited by 10 | Viewed by 6568

Abstract

The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached [...] Read more.

The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I–IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a–e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC₅₀ = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment. Full article

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Open AccessArticle

Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors

by Dong-Jun Fu, Ji-Feng Liu, Ruo-Han Zhao, Jia-Huan Li, Sai-Yang Zhang and Yan-Bing Zhang

Molecules 2017, 22(9), 1470; https://doi.org/10.3390/molecules22091470 - 5 Sep 2017

Cited by 21 | Viewed by 5542

Abstract

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate [...] Read more.

A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure-activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC₅₀ value of 4.08 μM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 μM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents. Full article

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Open AccessReview

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

by Markos-Orestis Georgiadis, Olga Karoutzou, Angeliki-Sofia Foscolos and Ioannis Papanastasiou

Molecules 2017, 22(9), 1408; https://doi.org/10.3390/molecules22091408 - 25 Aug 2017

Cited by 41 | Viewed by 8489

Abstract

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have [...] Read more.

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy. Full article

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Open AccessArticle

Anticancer Activity of Ramalin, a Secondary Metabolite from the Antarctic Lichen Ramalina terebrata, against Colorectal Cancer Cells

by Sung-Suk Suh, Tai Kyoung Kim, Jung Eun Kim, Ju-Mi Hong, Trang Thu Thi Nguyen, Se Jong Han, Ui Joung Youn, Joung Han Yim and Il-Chan Kim

Molecules 2017, 22(8), 1361; https://doi.org/10.3390/molecules22081361 - 17 Aug 2017

Cited by 27 | Viewed by 7316

Abstract

Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer [...] Read more.

Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer cells, making them promising candidates for new anticancer therapeutic drugs. The main objective of this study was to evaluate the anticancer capacities of ramalin, a secondary metabolite from the Antarctic lichen Ramalina terebrata, in the human colorectal cancer cell line HCT116. In this study, ramalin displayed concentration-dependent anticancer activity against HCT116 cells, significantly suppressing proliferation and inducing apoptosis. Furthermore, ramalin induced cell cycle arrest in the gap 2/mitosis (G2/M) phase through the modulation of hallmark genes involved in the G2/M phase transition, such as tumour protein p53 (TP53), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase 1 (CDK1) and cyclin B1 (CCNB1). At both the transcriptional and translational level, ramalin caused a gradual increase in the expression of TP53 and its downstream gene CDKN1A, while decreasing the expression of CDK1 and CCNB1 in a concentration-dependent manner. In addition, ramalin significantly inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that ramalin may be a therapeutic candidate for the targeted therapy of colorectal cancer. Full article

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Open AccessArticle

Novel Methylselenoesters as Antiproliferative Agents

by Nuria Díaz-Argelich, Ignacio Encío, Daniel Plano, Aristi P. Fernandes, Juan Antonio Palop and Carmen Sanmartín

Molecules 2017, 22(8), 1288; https://doi.org/10.3390/molecules22081288 - 2 Aug 2017

Cited by 16 | Viewed by 6124

Abstract

Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH₃SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with [...] Read more.

Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH₃SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with different scaffolds aiming to modulate the release of CH₃SeH. The fifteen compounds follow Lipinski’s Rule of Five and with exception of compounds 1 and 14, present better drug-likeness values than the positive control methylseleninic acid. The compounds were evaluated to determine their radical scavenging activity. Compound 11 reduced both DPPH and ABTS radicals. The cytotoxicity of the compounds was evaluated in a panel of five cancer cell lines (prostate, colon and lung carcinoma, mammary adenocarcinoma and chronic myelogenous leukemia) and two non-malignant (lung and mammary epithelial) cell lines. Ten compounds had GI₅₀ values below 10 μM at 72 h in four cancer cell lines. Compounds 5 and 15 were chosen for further characterization of their mechanism of action in the mammary adenocarcinoma cell line due to their similarity with methylseleninic acid. Both compounds induced G₂/M arrest whereas cell death was partially executed by caspases. The reduction and metabolism were also investigated, and both compounds were shown to be substrates for redox active enzyme thioredoxin reductase. Full article

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Open AccessReview

Research Progress in the Modification of Quercetin Leading to Anticancer Agents

by Alessandro Massi, Olga Bortolini, Daniele Ragno, Tatiana Bernardi, Gianni Sacchetti, Massimo Tacchini and Carmela De Risi

Molecules 2017, 22(8), 1270; https://doi.org/10.3390/molecules22081270 - 29 Jul 2017

Cited by 187 | Viewed by 13289

Abstract

The flavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin [...] Read more.

The flavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin can prevent neurological disorders and exerts protection against mitochondrial damages. Various in vitro studies have assessed the anticancer effects of quercetin, although there are no conclusive data regarding its mode of action. However, low bioavailability, poor aqueous solubility as well as rapid body clearance, fast metabolism and enzymatic degradation hamper the use of quercetin as therapeutic agent, so intense research efforts have been focused on the modification of the quercetin scaffold to obtain analogs with potentially improved properties for clinical applications. This review gives an overview of the developments in the synthesis and anticancer-related activities of quercetin derivatives reported from 2012 to 2016. Full article

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Newly Synthesized Doxorubicin Complexes with Selected Metals—Synthesis, Structure and Anti-Breast Cancer Activity

by Agata Jabłońska-Trypuć, Grzegorz Świderski, Rafał Krętowski and Włodzimierz Lewandowski

Molecules 2017, 22(7), 1106; https://doi.org/10.3390/molecules22071106 - 4 Jul 2017

Cited by 62 | Viewed by 8214

Abstract

Doxorubicin (DOX) is very effective chemotherapeutic agent, however it has several major drawbacks. Therefore the motivation for developing novel drug complexes as anticancer agents with different mechanism of action has arisen. The aim of the present study was to evaluate the influence of [...] Read more.

Doxorubicin (DOX) is very effective chemotherapeutic agent, however it has several major drawbacks. Therefore the motivation for developing novel drug complexes as anticancer agents with different mechanism of action has arisen. The aim of the present study was to evaluate the influence of newly synthesized DOX complexes with selected metals (Mg, Mn, Co, Ni, Fe, Cu, Zn) on apoptosis, cell cycle, viability, proliferation and cytotoxicity in the breast cancer cell line MCF-7. Complexation of DOX with metals has likewise been the subject of our research. The current work showed that the tested bivalent metals at a given pH condition formed metal:DOX complexes in a ratio of 2:1, while iron complexes with DOX in a ratio of 3:1. The studies also showed that selected metal-DOX complexes (Mg-DOX, Mn-DOX, Ni-DOX) at 0.5 µM concentration significantly decreased cell viability and proliferation, however they increased caspase 7 activity. Results also indicated that studied metal-DOX complexes showed high cytotoxicity in MCF-7 cells. Therefore they were chosen for cell cycle check-points and apoptosis/necrosis analysis studied by flow cytometry. Obtained results suggest that doxorubicin complexed by specified metals can be considered as a potential anti-breast cancer agent, which is characterized by a higher efficacy than a parent drug. Full article

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Open AccessArticle

Determination of Structural Requirements of N-Substituted Tetrahydro-β-Carboline Imidazolium Salt Derivatives Using in Silico Approaches for Designing MEK-1 Inhibitors

by Jingwei Liang, Mingyang Wang, Xinyang Li, Xin He, Chong Cao and Fanhao Meng

Molecules 2017, 22(6), 1020; https://doi.org/10.3390/molecules22061020 - 19 Jun 2017

Cited by 6 | Viewed by 5614

Abstract

Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the [...] Read more.

Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q² value of 0.700; r² value of 0.954; with 5 optimum components. The database alignment was utilized for building the CoMSIA model, and the CoMSIA model had q² and r² values of 0.615 and 0.897, with 4 optimum components. Target fishing of the PharmMapper platform was utilised for finding potential targets, the human mitogen-activated protein kinase 1 (MEK-1) was found to be the primary potential target for the three compounds with the fit scores of 6.288, 5.741, and 6.721. The molecular docking technique of MOE 2015 was carried out to identify the interactions of amino acids surrounding the ligand, and correlating QASR contour maps were used to identify structural requirements of N-substituted tetrahydro-β-carboline imidazolium salt moieties. Molecular dynamics and simulation studies proved that the target protein was stable for 0.8–5 ns. The pivotal moieties of N-substituted tetrahydro-β-carboline imidazolium salt derivatives and its potential targets were verified by the QASR study, PharmMapper, and the molecular docking study which would be helpful to design novel MEK-1 inhibitors for anticancer drugs. Full article

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Open AccessArticle

Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells

by Lei Zhang, Jing Wang, Lai Liu, Chengyue Zheng and Yang Wang

Molecules 2017, 22(4), 628; https://doi.org/10.3390/molecules22040628 - 17 Apr 2017

Cited by 18 | Viewed by 6117

Abstract

With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell [...] Read more.

With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, P-A, exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC₅₀ values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, P-A efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively. Further mechanism studies revealed that P-A could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, P-A inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of P-A were similar to those of precursor PPT but different with the other precursor ATRA. Together, the conjugate P-A was a promising candidate for the potential treatment of human gastric cancer. Full article

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Open AccessArticle

Design, Synthesis and Evaluation of Naphthalimide Derivatives as Potential Anticancer Agents for Hepatocellular Carcinoma

by Chaochao Ge, Liping Chang, Ying Zhao, Congcong Chang, Xiaojuan Xu, Haoying He, Yuxia Wang, Fujun Dai, Songqiang Xie and Chaojie Wang

Molecules 2017, 22(2), 342; https://doi.org/10.3390/molecules22020342 - 22 Feb 2017

Cited by 22 | Viewed by 6682

Abstract

Two kinds of naphthalimide derivatives were synthesized and evaluated for in vitro their anti-hepatocellular carcinoma properties. Compound 3a with a fused thiazole fragment to naphthalimide skeleton inhibited cell migration of SMMC-7721 and HepG2, and further in vivo trials with two animal models confirmed [...] Read more.

Two kinds of naphthalimide derivatives were synthesized and evaluated for in vitro their anti-hepatocellular carcinoma properties. Compound 3a with a fused thiazole fragment to naphthalimide skeleton inhibited cell migration of SMMC-7721 and HepG2, and further in vivo trials with two animal models confirmed that compound 3a moderately inhibited primary H22 tumor growth (52.6%) and potently interrupted lung metastasis (75.7%) without obvious systemic toxicity at the therapeutic dose. Mechanistic research revealed that compound 3a inhibited cancerous liver cell growth mostly by inducing G2/M phase arrest. Western blotting experiments corroborated that 3a could up-regulate the cell cycle related protein expression of cyclin B1, CDK1 and p21, and inhibit cell migration by elevating the E-cadherin and attenuating integrin α6 expression. Our study showed that compound 3a is a valuable lead compound worthy of further investigation. Full article

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Targeting Cancer Stem Cells with Novel 4-(4-Substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thiones

by Mashooq Ahmad Bhat, Abdullah Al-Dhfyan and Mohamed A. Al-Omar

Molecules 2016, 21(12), 1746; https://doi.org/10.3390/molecules21121746 - 19 Dec 2016

Cited by 24 | Viewed by 5995

Abstract

Novel 4-(4-substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thione derivatives (DHP 1–9) were designed, synthesized, characterized and evaluated for antitumor activity against cancer stem cells. The compounds were synthesized in one pot. Enaminones E1 and E2 were reacted with substituted benzaldehydes and urea/thiourea [...] Read more.

Novel 4-(4-substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thione derivatives (DHP 1–9) were designed, synthesized, characterized and evaluated for antitumor activity against cancer stem cells. The compounds were synthesized in one pot. Enaminones E1 and E2 were reacted with substituted benzaldehydes and urea/thiourea in the presence of glacial acetic acid. The synthesized compounds were characterized by spectral analysis. The compounds were screened in vitro against colon cancer cell line (LOVO) colon cancer stem cells. Most of the compounds were found to be active against side population cancer stem cells with an inhibition of >50% at a 10 μM concentration. Compounds DHP-1, DHP-7 and DHP-9 were found to be inactive. Compound DHP-5 exhibited an in vitro anti-proliferative effect and arrested cancer cells at the Gap 2 phase (G2) checkpoint and demonstrated an inhibitory effect on tumor growth for a LOVO xenograft in a nude mouse experiment. Full article

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Open AccessReview

The HK2 Dependent “Warburg Effect” and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate

by Paweł Lis, Mariusz Dyląg, Katarzyna Niedźwiecka, Young H. Ko, Peter L. Pedersen, Andre Goffeau and Stanisław Ułaszewski

Molecules 2016, 21(12), 1730; https://doi.org/10.3390/molecules21121730 - 15 Dec 2016

Cited by 162 | Viewed by 22206

Abstract

This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the “Warburg” and “Crabtree” effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the [...] Read more.

This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the “Warburg” and “Crabtree” effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the “Warburg effect” and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the “Warburg effect”, and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the “Warburg effect”, i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as “multiple myeloma”. Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development. Full article

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Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel Primaquine-Cinnamic Acid Conjugates of the Amide and Acylsemicarbazide Type

by Kristina Pavić, Ivana Perković, Petra Gilja, Filip Kozlina, Katja Ester, Marijeta Kralj, Dominique Schols, Dimitra Hadjipavlou-Litina, Eleni Pontiki and Branka Zorc

Molecules 2016, 21(12), 1629; https://doi.org/10.3390/molecules21121629 - 28 Nov 2016

Cited by 27 | Viewed by 8490

Abstract

In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds 3a–k) or via a spacer (compounds 7a–k) are reported. In the first series of compounds, PQ [...] Read more.

In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds 3a–k) or via a spacer (compounds 7a–k) are reported. In the first series of compounds, PQ and various CADs were connected by amide bonds and in the second series by acylsemicarbazide functional groups built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs. PQ-CAD amides 3a–k were prepared by a simple one-step condensation reaction of PQ with a series of CAD chlorides (method A) or benzotriazolides 2 (method B). The synthesis of acylsemicarbazides 7a–k included activation of PQ with benzotriazole, preparation of PQ-semicarbazide 6 and its condensation with CAD chlorides 4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series 3 were selective towards the MCF-7 cell line and active at micromolar concentrations. The o-fluoro derivative 3h showed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide 7f with a benzodioxole ring and 7c, 7g and especially 7j with methoxy-, chloro- or trifluoromethyl-substituents in the para position showed high selectivity and high inhibitory activity against MCF-7 cell line at micromolar (7c, 7f, 7g) and nanomolar (7j) levels. Acylsemicarbazide derivatives with trifluoromethyl group(s) 7i, 7j and 7k showed specific activity against human coronavirus (229E) at concentrations which did not alter the normal cell morphology. The same compounds exerted the most potent reducing activity in the DPPH test, together with 7d and 7g, while methoxy (compounds 7c–e), benzodioxole (7f), p-Cl (7g) and m-CF₃ (7i) acylsemicarbazides and amide 3f presented the highest LP inhibition (83%–89%). The dimethoxy derivative 7d was the most potent LOX inhibitor (IC₅₀ = 10 μΜ). The performed biological tests gave evidence of acylsemicarbazide functional group as superior binding group in PQ-CAD conjugates. Full article

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Open AccessArticle

Transdermal Permeation and Anti-Inflammation Activities of Novel Sinomenine Derivatives

by Zi-Jian Zhao, Chang Zhao, Jing Xiao and Jian-Cheng Wang

Molecules 2016, 21(11), 1520; https://doi.org/10.3390/molecules21111520 - 17 Nov 2016

Cited by 14 | Viewed by 4971

Abstract

Sinomenine is extracted from Sinomenii caulis (a traditional Chinese medicine), and it is used as the active ingredient in rheumatic arthritis treatments. It has been used in clinical applications for decades. However, there are some disadvantages, including low activity in transdermal permeation and [...] Read more.

Sinomenine is extracted from Sinomenii caulis (a traditional Chinese medicine), and it is used as the active ingredient in rheumatic arthritis treatments. It has been used in clinical applications for decades. However, there are some disadvantages, including low activity in transdermal permeation and a high dosage being clinically required. To overcome these defects, sinomenine was used as a primer, and structural modification was performed. In our study, eight new compounds were screened out by transdermal permeation in vitro and anti-inflammatory response in vitro and in vivo. Compound 1a exhibited the most potent transdermal permeation and anti-inflammatory activity. Based on these results, further development of this compound may be warranted. Full article

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Open AccessReview

Mitoxantrone-Surfactant Interactions: A Physicochemical Overview

by Mirela Enache, Ana Maria Toader and Madalin Iancu Enache

Molecules 2016, 21(10), 1356; https://doi.org/10.3390/molecules21101356 - 13 Oct 2016

Cited by 44 | Viewed by 8696

Abstract

Mitoxantrone is a synthetic anticancer drug used clinically in the treatment of different types of cancer. It was developed as a doxorubicin analogue in a program to find drugs with improved antitumor activity and decreased cardiotoxicity compared with the anthracyclines. As the cell [...] Read more.

Mitoxantrone is a synthetic anticancer drug used clinically in the treatment of different types of cancer. It was developed as a doxorubicin analogue in a program to find drugs with improved antitumor activity and decreased cardiotoxicity compared with the anthracyclines. As the cell membrane is the first barrier encountered by anticancer drugs before reaching the DNA sites inside the cells and as surfactant micelles are known as simple model systems for biological membranes, the drugs-surfactant interaction has been the subject of great research interest. Further, quantitative understanding of the interactions of drugs with biomimicking structures like surfactant micelles may provide helpful information for the control of physicochemical properties and bioactivities of encapsulated drugs in order to design better delivery systems with possible biomedical applications. The present review describes the physicochemical aspects of the interactions between the anticancer drug mitoxantrone and different surfactants. Mitoxantrone-micelle binding constants, partitions coefficient of the drug between aqueous and micellar phases and the corresponding Gibbs free energy for the above processes, and the probable location of drug molecules in the micelles are discussed. Full article

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Open AccessArticle

Modulation of Autophagy by a Thioxanthone Decreases the Viability of Melanoma Cells

by Raquel T. Lima, Diana Sousa, Ana M. Paiva, Andreia Palmeira, João Barbosa, Madalena Pedro, Madalena M. Pinto, Emília Sousa and M. Helena Vasconcelos

Molecules 2016, 21(10), 1343; https://doi.org/10.3390/molecules21101343 - 10 Oct 2016

Cited by 33 | Viewed by 6408

Abstract

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to [...] Read more.

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N¹⁰-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI₅₀ concentration (3.6 μM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity. Full article

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Open AccessArticle

Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma

by Hwan Hee Lee, Seulki Lee, Yu Su Shin, Miyeon Cho, Hyojeung Kang and Hyosun Cho

Molecules 2016, 21(10), 1286; https://doi.org/10.3390/molecules21101286 - 26 Sep 2016

Cited by 38 | Viewed by 8714

Abstract

Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, [...] Read more.

Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, the most abundant flavonoid, has been shown to have anti-ulcer, anti-cancer, antioxidant, and anti-inflammatory properties. Latent Epstein-Barr virus (EBV) infection can lead to serious malignancies, such as, Burkitt’s lymphoma, Hodgkin’s disease and gastric carcinoma(GC), and (Epstein-Barr virus associated gastric carcinoma) EBVaGC is one of the most common EBV-associated cancers. In this study, the authors first examined the anti-cancer effects of quercetin and isoliquiritigenin in vivo xenograft animal models implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(−) human gastric carcinoma (MKN74), and then explored the molecular mechanisms responsible for their anti-cancer activities. The results obtained showed that anti-cancer effect of quercetin was greater than isoliquiritigenin in mice injected with EBV(+) human gastric carcinoma (SNU719) cells. On the other hand, quercetin and isoliquiritigenin had similar anti-cancer effects in mice injected with EBV(−) human gastric carcinoma (MKN74) cells. Interestingly, quercetin inhibited EBV viral protein expressions, including EBNA-1 and LMP-2 proteins in tumor tissues from mice injected with EBV(+) human gastric carcinoma. Quercetin more effectively induced p53-dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this induction was correlated with increased expressions of the cleaved forms of caspase-3, -9, and Parp. In EBV(−)human gastric carcinoma (MKN74), both quercetin and isoliquiritigenin induced the expressions of p53, Bax, and Puma and the cleaved forms of caspase-3 and -9 and Parp at similar levels. Full article

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Open AccessArticle

Copper Ion Attenuated the Antiproliferative Activity of Di-2-pyridylhydrazone Dithiocarbamate Derivative; However, There Was a Lack of Correlation between ROS Generation and Antiproliferative Activity

by Tingting Wang, Yun Fu, Tengfei Huang, Youxun Liu, Meihao Wu, Yanbin Yuan, Shaoshan Li and Changzheng Li

Molecules 2016, 21(8), 1088; https://doi.org/10.3390/molecules21081088 - 20 Aug 2016

Cited by 19 | Viewed by 6681

Abstract

The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying [...] Read more.

The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC₅₀ = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20–30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA–Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA–Cu lacked this effect, which explained the difference in their antiproliferative activity. Full article

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Open AccessArticle

Hybrid Molecules Containing a 7-Chloro-4-aminoquinoline Nucleus and a Substituted 2-Pyrazoline with Antiproliferative and Antifungal Activity

by Alba Montoya, Jairo Quiroga, Rodrigo Abonia, Marcos Derita, Maximiliano Sortino, Alfredo Ornelas, Susana Zacchino and Braulio Insuasty

Molecules 2016, 21(8), 969; https://doi.org/10.3390/molecules21080969 - 27 Jul 2016

Cited by 22 | Viewed by 5564

Abstract

Twenty-four new hybrid analogues (15–38) containing 7-chloro-4-aminoquinoline and 2-pyrazoline N-heterocyclic fragments were synthesized. Twelve of the new compounds were evaluated against 58 human cancer cell lines by the U.S. National Cancer Institute (NCI). Compounds 25, 30, 31 [...] Read more.

Twenty-four new hybrid analogues (15–38) containing 7-chloro-4-aminoquinoline and 2-pyrazoline N-heterocyclic fragments were synthesized. Twelve of the new compounds were evaluated against 58 human cancer cell lines by the U.S. National Cancer Institute (NCI). Compounds 25, 30, 31, 36, and 37 showed significant cytostatic activity, with the most outstanding GI₅₀ values ranging from 0.05 to 0.95 µM. The hybrid compounds (15–38) were also evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. From the obtained results some structure–activity relationships were outlined. Full article

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Open AccessArticle

Synthesis, Characterization and Anti-Cancer Activity of Hydrazide Derivatives Incorporating a Quinoline Moiety

by Murat Bingul, Owen Tan, Christopher R. Gardner, Selina K. Sutton, Greg M. Arndt, Glenn M. Marshall, Belamy B. Cheung, Naresh Kumar and David StC. Black

Molecules 2016, 21(7), 916; https://doi.org/10.3390/molecules21070916 - 14 Jul 2016

Cited by 68 | Viewed by 13424

Abstract

Identification of the novel (E)-N′-((2-chloro-7-methoxyquinolin-3-yl)methylene)-3-(phenylthio)propanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19–26 were prepared from the corresponding quinoline hydrazones [...] Read more.

Identification of the novel (E)-N′-((2-chloro-7-methoxyquinolin-3-yl)methylene)-3-(phenylthio)propanehydrazide scaffold 18 has led to the development of a new series of biologically active hydrazide compounds. The parent compound 18 and new quinoline derivatives 19–26 were prepared from the corresponding quinoline hydrazones and substituted carboxylic acids using EDC-mediated peptide coupling reactions. Further modification of the parent compound 18 was achieved by replacement of the quinoline moiety with other aromatic systems. All the newly synthesized compounds were evaluated for their anti-cancer activity against the SH-SY5Y and Kelly neuroblastoma cell lines, as well as the MDA-MB-231 and MCF-7 breast adenocarcinoma cell lines. Analogues 19 and 22 significantly reduced the cell viability of neuroblastoma cancer cells with micromolar potency and significant selectivity over normal cells. The quinoline hydrazide 22 also induced G₁ cell cycle arrest, as well as upregulation of the p27^kip1 cell cycle regulating protein. Full article

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Open AccessArticle

Pyridine and p-Nitrophenyl Oxime Esters with Possible Photochemotherapeutic Activity: Synthesis, DNA Photocleavage and DNA Binding Studies

by Milena Pasolli, Konstantinos Dafnopoulos, Nicolaos-Panagiotis Andreou, Panagiotis S. Gritzapis, Maria Koffa, Alexandros E. Koumbis, George Psomas and Konstantina C. Fylaktakidou

Molecules 2016, 21(7), 864; https://doi.org/10.3390/molecules21070864 - 30 Jun 2016

Cited by 17 | Viewed by 7703

Abstract

Compared to standard treatments for various diseases, photochemotherapy and photo-dynamic therapy are less invasive approaches, in which DNA photocleavers represent promising tools for novel “on demand” chemotherapeutics. A series of p-nitrobenzoyl and p-pyridoyl ester conjugated aldoximes, amidoximes and ethanone oximes were [...] Read more.

Compared to standard treatments for various diseases, photochemotherapy and photo-dynamic therapy are less invasive approaches, in which DNA photocleavers represent promising tools for novel “on demand” chemotherapeutics. A series of p-nitrobenzoyl and p-pyridoyl ester conjugated aldoximes, amidoximes and ethanone oximes were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA. The compounds which possessed appropriate properties were additionally subjected to UVA irradiation at 365 nm. The ability of most of the compounds to photocleave DNA was high at 312 nm, whereas higher concentrations were required at 365 nm as a result of their lower UV absorption. The affinity of selected compounds to calf-thymus (CT) DNA was studied by UV spectroscopy, viscosity experiments and competitive studies with ethidium bromide (EB) revealing that all compounds interacted with CT DNA. The fluorescence emission spectra of the pre-treated EB-DNA exhibited a moderate to significant quenching in the presence of the compounds indicating the binding of the compounds to CT DNA via intercalation as concluded also by DNA-viscosity experiments. For the oxime esters the DNA photocleavage and affinity studies aimed to clarify the role of the oxime nature (aldoxime, ketoxime, amidoxime) and the role of the pyridine and p-nitrophenyl moieties both as oxime substituents and ester conjugates. Full article

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Open AccessArticle

Novel 5-Substituted 2-(Aylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides: Synthesis, Molecular Structure, Anticancer Activity, Apoptosis-Inducing Activity and Metabolic Stability

by Beata Żołnowska, Jarosław Sławiński, Aneta Pogorzelska, Krzysztof Szafrański, Anna Kawiak, Grzegorz Stasiłojć, Mariusz Belka, Szymon Ulenberg, Tomasz Bączek and Jarosław Chojnacki

Molecules 2016, 21(6), 808; https://doi.org/10.3390/molecules21060808 - 22 Jun 2016

Cited by 17 | Viewed by 7475

Abstract

A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27–60 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell [...] Read more.

A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27–60 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC₅₀ values below 100 μM. It was found that for the analogues 36–38 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R² and Ar = 4-CF₃-C₆H₄ moiety in 2-(R²-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC₅₀ = 36 μM), HeLa (IC₅₀ = 34 μM) cell lines, apoptosis-inducing activity and moderate metabolic stability. Full article

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Open AccessArticle

Discovery of Novel Allopurinol Derivatives with Anticancer Activity and Attenuated Xanthine Oxidase Inhibition

by Yong Li, Ting-Ting Cao, Shanchun Guo, Qiu Zhong, Cai-Hu Li, Ying Li, Lin Dong, Shilong Zheng, Guangdi Wang and Shu-Fan Yin

Molecules 2016, 21(6), 771; https://doi.org/10.3390/molecules21060771 - 20 Jun 2016

Cited by 14 | Viewed by 8018

Abstract

A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC₅₀ [...] Read more.

A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC₅₀ values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC₅₀ values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility. Full article

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Open AccessArticle

Synthesis and Cytotoxic Activity of Biphenylurea Derivatives Containing Indolin-2-one Moieties

by Wagdy M. Eldehna, Mohamed Fares, Hany S. Ibrahim, Muhammad A. Alsherbiny, Mohamed H. Aly, Hazem A. Ghabbour and Hatem A. Abdel-Aziz

Molecules 2016, 21(6), 762; https://doi.org/10.3390/molecules21060762 - 10 Jun 2016

Cited by 38 | Viewed by 6954

Abstract

In our endeavor towards the development of potent anticancer agents, two different sets of biphenylurea-indolinone conjugates, 5a–s and 8a,b were synthesized. The in vitro cytotoxicity of the synthesized compounds was examined in two human cancer cell lines, namely MCF-7 [...] Read more.

In our endeavor towards the development of potent anticancer agents, two different sets of biphenylurea-indolinone conjugates, 5a–s and 8a,b were synthesized. The in vitro cytotoxicity of the synthesized compounds was examined in two human cancer cell lines, namely MCF-7 breast cancer and PC-3 prostate cancer cells using the sulforhodamine B (SRB) colorimetric assay. In particular, the MCF-7 cancer cell line was more susceptible to the synthesized compounds. Compound 5o (IC₅₀ = 1.04 ± 0.10 μM) emerged as the most active member in this study against MCF-7, with 7-fold increased activity compared to the reference drug, doxorubicin (IC₅₀ = 7.30 ± 0.84 μM). Compounds 5l, 5q and 8b also exhibited superior cytotoxic activity against MCF-7 with IC₅₀ values of 1.93 ± 0.17, 3.87 ± 0.31 and 4.66 ± 0.42 μM, respectively. All of the tested compounds were filtered according to the Lipinski and Veber rules and all of them passed the filters. Additionally, several ADME descriptors for the synthesized compounds 5a–s and 8a,b were predicted via a theoretical kinetic study performed using the Discovery Studio 2.5 software. Full article

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Open AccessArticle

Design, Synthesis and Structure-Activity Relationships of Novel Chalcone-1,2,3-triazole-azole Derivates as Antiproliferative Agents

by Sai-Yang Zhang, Dong-Jun Fu, Xiao-Xin Yue, Ying-Chao Liu, Jian Song, Hui-Hui Sun, Hong-Min Liu and Yan-Bing Zhang

Molecules 2016, 21(5), 653; https://doi.org/10.3390/molecules21050653 - 19 May 2016

Cited by 55 | Viewed by 8622

Abstract

A series of novel chalcone-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, EC-109 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, [...] Read more.

A series of novel chalcone-1,2,3-triazole-azole hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, EC-109 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound I-21 showed the most excellent antiproliferative activity with an IC₅₀ value of 1.52 μM against SK-N-SH cancer cells. Further mechanism studies revealed that compound I-21 induced morphological changes of SK-N-SH cancer cells possibly by inducing apoptosis. Novel chalcone-1,2,3-triazole-azole derivatives in this work might be a series of promising lead compounds to develop anticancer agents for treating neuroblastoma. Full article

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Open AccessArticle

Synthesis and Biological Testing of Novel Glucosylated Epigallocatechin Gallate (EGCG) Derivatives

by Xin Zhang, Jing Wang, Jiang-Miao Hu, Ye-Wei Huang, Xiao-Yun Wu, Cheng-Ting Zi, Xuan-Jun Wang and Jun Sheng

Molecules 2016, 21(5), 620; https://doi.org/10.3390/molecules21050620 - 11 May 2016

Cited by 42 | Viewed by 9656

Abstract

Epigallocatechin gallate (EGCG) is the most abundant component of green tea catechins and has strong physiological activities. In this study, two novel EGCG glycosides (EGCG-G1 and EGCG-G2) were chemoselectively synthesized by a chemical modification strategy. Each of these EGCG glycosides underwent structure identification, [...] Read more.

Epigallocatechin gallate (EGCG) is the most abundant component of green tea catechins and has strong physiological activities. In this study, two novel EGCG glycosides (EGCG-G1 and EGCG-G2) were chemoselectively synthesized by a chemical modification strategy. Each of these EGCG glycosides underwent structure identification, and the structures were assigned as follows: epigallocatechin gallate-4′′-O-β-d-glucopyranoside (EGCG-G1, 2) and epigallocatechin gallate-4′,4′′-O-β-d-gluco-pyranoside (EGCG-G2, 3). The EGCG glycosides were evaluated for their anticancer activity in vitro against two human breast cell lines (MCF-7 and MDA-MB-231) using MTT assays. The inhibition rate of EGCG glycosides (EGCG-G1 and EGCG-G2) is not obvious. The EGCG glycosides are more stable than EGCG in aqueous solutions, but exhibited decreasing antioxidant activity in the DPPH radical-scavenging assay (EGCG > EGCG-G2 > EGCG-G1). Additionally, the EGCG glycosides exhibited increased water solubility: EGCG-G2 and EGCG-G1 were 15 and 31 times as soluble EGCG, respectively. The EGCG glycosides appear to be useful, and further studies regarding their biological activity are in progress. Full article

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Open AccessArticle

Novel N-Substituted 2-(2-(Adamantan-1-yl)-1H-Indol-3-yl)-2-Oxoacetamide Derivatives: Synthesis and Biological Evaluation

by Hong-Yu Hu, Xu-Dong Yu, Fei Wang, Chun-Rong Lin, Jin-Zhang Zeng, Ying-Kun Qiu, Mei-Juan Fang and Zhen Wu

Molecules 2016, 21(5), 530; https://doi.org/10.3390/molecules21050530 - 5 May 2016

Cited by 4 | Viewed by 6278

Abstract

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent [...] Read more.

In this study, a series of novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives were synthesized, and evaluated for their cytotoxicity in human cell lines including Hela (cervical cancer), MCF7 (breast cancer ) and HepG2 (liver cancer). Several compounds were found to have potent anti-proliferative activity against those human cancer cell lines and compound 5r showed the most potent biological activity against HepG2 cells with an IC₅₀ value of 10.56 ± 1.14 μΜ. In addition, bioassays showed that compound 5r induced time-dependent and dose-dependent cleavage of poly ADP-ribose polymerase (PARP), and also induced a dose-dependent increase in caspase-3 and caspase-8 activity, but had little effect on caspase-9 protease activity in HepG2 cells. These results provide evidence that 5r-induced apoptosis in HepG2 cell is caspase-8-dependent. Full article

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Open AccessArticle

Delivery of Gemcitabine Prodrugs Employing Mesoporous Silica Nanoparticles

by Alessio Malfanti, Ivana Miletto, Emanuela Bottinelli, Daniele Zonari, Giulia Blandino, Gloria Berlier and Silvia Arpicco

Molecules 2016, 21(4), 522; https://doi.org/10.3390/molecules21040522 - 21 Apr 2016

Cited by 33 | Viewed by 7759

Abstract

In this paper, mesoporous silica nanoparticles (MSNs) were studied as vehicles for the delivery of the antitumoral drug gemcitabine (GEM) and of its 4-(N)-acyl derivatives, (4-(N)-valeroyl-(C5GEM), 4-(N)-lauroyl-(C12GEM) and 4-(N)-stearoyl-gemcitabine (C18GEM)). The loading of the GEM [...] Read more.

In this paper, mesoporous silica nanoparticles (MSNs) were studied as vehicles for the delivery of the antitumoral drug gemcitabine (GEM) and of its 4-(N)-acyl derivatives, (4-(N)-valeroyl-(C5GEM), 4-(N)-lauroyl-(C12GEM) and 4-(N)-stearoyl-gemcitabine (C18GEM)). The loading of the GEM lipophilic prodrugs on MSNs was explored with the aim to obtain both a physical and a chemical protection of GEM from rapid plasmatic metabolization. For this purpose, MSNs as such or with grafted aminopropyl and carboxyethyl groups were prepared and characterized. Then, their different drug loading capacity in relation to the nature of the functional group was evaluated. In our experimental conditions, GEM was not loaded in any MSNs, while C12GEM was the most efficiently encapsulated and employed for further evaluation. The results showed that loading capacity increased with the presence of functional groups on the nanoparticles; similarly, the presence of functional groups on MSNs’ surface influenced the drug release profile. Finally, the cytotoxicity of the different preparations was evaluated and data showed that C12GEM loaded MSNs are less cytotoxic than the free drug with an activity that increased with the incubating time, indicating that all these systems are able to release the drug in a controlled manner. Altogether, the results demonstrate that these MSNs could be an interesting system for the delivery of anticancer drugs. Full article

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Open AccessArticle

Synthesis and Antitumor Evaluation of Novel 5-Hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one Derivatives

by Guang Ouyang, Rongsheng Tong, Jinqi Li, Lan Bai, Liang Ouyang, Xingmei Duan, Fengqiong Li, Pin He, Jianyou Shi and Yuxin He

Molecules 2016, 21(4), 516; https://doi.org/10.3390/molecules21040516 - 20 Apr 2016

Cited by 6 | Viewed by 5903

Abstract

A series of novel 5-hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one derivatives bearing natural product substructures has been successfully synthesized and their antitumor activity studied. These newly synthesized derivatives were characterized by ¹H-NMR, ¹³C-NMR and high resolution mass spectral data, then [...] Read more.

A series of novel 5-hydrosulfonyl-1H-benzo[d]imidazol-2(3H)-one derivatives bearing natural product substructures has been successfully synthesized and their antitumor activity studied. These newly synthesized derivatives were characterized by ¹H-NMR, ¹³C-NMR and high resolution mass spectral data, then screened as antitumor agents against the A549, HCC1937, and MDA-MB-468 human tumor cell lines using MTT cell proliferation assays. The results show that some of these compounds can effectively inhibit the growth of these cancerous cells, with compound 5b being the best one (IC₅₀ = 2.6 μM). Flow cytometry data revealed that compound 5b induced apoptosis of HCC1937 cells with increased solution concentration. The structure and activity relationships (SAR) of these compounds is summarized. Full article

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Open AccessArticle

In-Vitro Anticancer Evaluation of Some Novel Thioureido-Benzensulfonamide Derivatives

by Mostafa M. Ghorab, Mansour S. Alsaid, Mohammed S. Al-Dosari, Marwa G. El-Gazzar and Ahmed H. Arbab

Molecules 2016, 21(4), 409; https://doi.org/10.3390/molecules21040409 - 25 Mar 2016

Cited by 11 | Viewed by 5352

Abstract

A novel series of sulfonamide derivatives (14 compounds) bearing thiourea moieties were efficiently synthesized and evaluated for their possible in vitro anticancer activity against four human tumor cell lines. The results indicated that compound 6 was the most potent, showing effectiveness on all [...] Read more.

A novel series of sulfonamide derivatives (14 compounds) bearing thiourea moieties were efficiently synthesized and evaluated for their possible in vitro anticancer activity against four human tumor cell lines. The results indicated that compound 6 was the most potent, showing effectiveness on all the tested cell lines. Compounds 7 and 10 also showed promising results. Full article

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Open AccessArticle

Anticancer Effects of Sinulariolide-Conjugated Hyaluronan Nanoparticles on Lung Adenocarcinoma Cells

by Kuan Yin Hsiao, Yi-Jhen Wu, Zi Nong Liu, Chin Wen Chuang, Han Hsiang Huang and Shyh Ming Kuo

Molecules 2016, 21(3), 297; https://doi.org/10.3390/molecules21030297 - 2 Mar 2016

Cited by 25 | Viewed by 7094

Abstract

Lung cancer is one of the most clinically challenging malignant diseases worldwide. Sinulariolide (SNL), extracted from the farmed coral species Sinularia flexibilis, has been used for suppressing malignant cells. For developing anticancer therapeutic agents, we aimed to find an alternative for non-small [...] Read more.

Lung cancer is one of the most clinically challenging malignant diseases worldwide. Sinulariolide (SNL), extracted from the farmed coral species Sinularia flexibilis, has been used for suppressing malignant cells. For developing anticancer therapeutic agents, we aimed to find an alternative for non-small cell lung cancer treatment by using SNL as the target drug. We investigated the SNL bioactivity on A549 lung cancer cells by conjugating SNL with hyaluronan nanoparticles to form HA/SNL aggregates by using a high-voltage electrostatic field system. SNL was toxic on A549 cells with an IC₅₀ of 75 µg/mL. The anticancer effects of HA/SNL aggregates were assessed through cell viability assay, apoptosis assays, cell cycle analyses, and western blotting. The size of HA/SNL aggregates was approximately 33–77 nm in diameter with a thin continuous layer after aggregating numerous HA nanoparticles. Flow cytometric analysis revealed that the HA/SNL aggregate-induced apoptosis was more effective at a lower SNL dose of 25 µg/mL than pure SNL. Western blotting indicated that caspases-3, -8, and -9 and Bcl-xL and Bax played crucial roles in the apoptotic signal transduction pathway. In summary, HA/SNL aggregates exerted stronger anticancer effects on A549 cells than did pure SNL via mitochondria-related pathways. Full article

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Open AccessArticle

Preparation and Biological Evaluation of Two Novel Platinum(II) Complexes Based on the Ligands of Dipicolyamine Bisphosphonate Esters

by Ling Qiu, Hong Liu, Ke Li, Gaochao Lv, Hui Yang, Xiaofeng Qin and Jianguo Lin

Molecules 2016, 21(3), 255; https://doi.org/10.3390/molecules21030255 - 24 Feb 2016

Cited by 8 | Viewed by 5933

Abstract

Two new platinum(II)-based complexes bearing a bone-targeting group were synthesized and characterized. They both have excellent affinity for hydroxyapatite (HA), which is abundant in human bone tissues. Their antitumor activities against five human cancer cell lines (U2OS, A549, HCT116, MDA-MB-231 and HepG2) were [...] Read more.

Two new platinum(II)-based complexes bearing a bone-targeting group were synthesized and characterized. They both have excellent affinity for hydroxyapatite (HA), which is abundant in human bone tissues. Their antitumor activities against five human cancer cell lines (U2OS, A549, HCT116, MDA-MB-231 and HepG2) were evaluated and compared with cisplatin (CDDP). Though the antitumor efficacies of new complexes are lower than that of CDDP, they show higher selectivity against the HepG2 hepatoma cell line than the L02 normal liver cell line. Morphology studies exhibited typical characteristics of cell apoptosis and the cell cycle distribution analysis indicated that the complexes can inhibit cancer cells by inducing cell cycle arrest at the G2/M phase, a similar mechanism of action to CDDP. Full article

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Open AccessArticle

Synthesis and Anticancer Activities of Glycyrrhetinic Acid Derivatives

by Yang Li, Ling Feng, Zhi-Fang Song, Hai-Bei Li and Qi-Yong Huai

Molecules 2016, 21(2), 199; https://doi.org/10.3390/molecules21020199 - 6 Feb 2016

Cited by 23 | Viewed by 6619

Abstract

A total of forty novel glycyrrhetinic acid (GA) derivatives were designed and synthesized. The cytotoxic activity of the novel compounds was tested against two human breast cancer cell lines (MCF-7, MDA-MB-231) in vitro by the MTT method. The evaluation results revealed that, in [...] Read more.

A total of forty novel glycyrrhetinic acid (GA) derivatives were designed and synthesized. The cytotoxic activity of the novel compounds was tested against two human breast cancer cell lines (MCF-7, MDA-MB-231) in vitro by the MTT method. The evaluation results revealed that, in comparison with GA, compound 42 shows the most promising anticancer activity (IC₅₀ 1.88 ± 0.20 and 1.37 ± 0.18 µM for MCF-7 and MDA-MB-231, respectively) and merits further exploration as a new anticancer agent. Full article

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Open AccessArticle

Design of a MCoTI-Based Cyclotide with Angiotensin (1-7)-Like Activity

by Teshome Aboye, Christopher J. Meeks, Subhabrata Majumder, Alexander Shekhtman, Kathleen Rodgers and Julio A. Camarero

Molecules 2016, 21(2), 152; https://doi.org/10.3390/molecules21020152 - 26 Jan 2016

Cited by 37 | Viewed by 6380

Abstract

We report for the first time the design and synthesis of a novel cyclotide able to activate the unique receptor of angiotensin (1-7) (AT1-7), the MAS1 receptor. This was accomplished by grafting an AT1-7 peptide analog onto loop 6 of cyclotide MCoTI-I using [...] Read more.

We report for the first time the design and synthesis of a novel cyclotide able to activate the unique receptor of angiotensin (1-7) (AT1-7), the MAS1 receptor. This was accomplished by grafting an AT1-7 peptide analog onto loop 6 of cyclotide MCoTI-I using isopeptide bonds to preserve the α-amino and C-terminal carboxylate groups of AT1-7, which are required for activity. The resulting cyclotide construct was able to adopt a cyclotide-like conformation and showed similar activity to that of AT1-7. This cyclotide also showed high stability in human serum thereby providing a promising lead compound for the design of a novel type of peptide-based in the treatment of cancer and myocardial infarction. Full article

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2015

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Open AccessArticle

Synthesis of Bioconjugate Sesterterpenoids with Phospholipids and Polyunsaturated Fatty Acids

by Ana Gil-Mesón, Alejandro M. Roncero, Ignacio E. Tobal, Pilar Basabe, David Díez, Faustino Mollinedo and Isidro S. Marcos

Molecules 2016, 21(1), 47; https://doi.org/10.3390/molecules21010047 - 30 Dec 2015

Cited by 8 | Viewed by 6662

Abstract

A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) [...] Read more.

A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) are obtained varying the sesterterpenoid in position 1 or 2 of the glycerol or a phosphocholine or PUFA unit in position 3. Simple bioconjugates of sesterterpenoids and eicosapentaenoic acid (EPA) have been obtained too. All synthetic derivatives were tested against the human tumour cell lines HeLa (cervix) and MCF-7 (breast). Some compounds showed good IC₅₀ (0.3 and 0.2 μM) values against these cell lines. Full article

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Open AccessArticle

Synthesis of Novel Pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxide Derivatives with Potential Anticancer Activity

by Jarosław Sławiński, Aleksandra Grzonek, Beata Żołnowska and Anna Kawiak

Molecules 2016, 21(1), 41; https://doi.org/10.3390/molecules21010041 - 29 Dec 2015

Cited by 7 | Viewed by 5908

Abstract

A series of novel 3-/2,3-substituted pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxides 4–28 have been synthesized by the reaction of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate [...] Read more.

A series of novel 3-/2,3-substituted pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxides 4–28 have been synthesized by the reaction of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate anticancer activity toward human cancer cell lines, HCT-116, MCF-7 and HeLa. The structure of this novel heterocyclic ring system was confirmed by ¹D-NMR and ²D-NMR spectroscopic data including COSY, ROESY and HMBC, elemental analyses and MS spectrometry. Full article

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Open AccessReview

Chemoprevention of Breast Cancer by Dietary Polyphenols

by Maria-Magdalena Mocanu, Péter Nagy and János Szöllősi

Molecules 2015, 20(12), 22578-22620; https://doi.org/10.3390/molecules201219864 - 17 Dec 2015

Cited by 86 | Viewed by 33328

Abstract

The review will discuss in detail the effects of polyphenols on breast cancer, including both the advantages and disadvantages of the applications of these natural compounds. First, we focus on the characterization of the main classes of polyphenols and then on in vitro [...] Read more.

The review will discuss in detail the effects of polyphenols on breast cancer, including both the advantages and disadvantages of the applications of these natural compounds. First, we focus on the characterization of the main classes of polyphenols and then on in vitro and in vivo experiments carried out in breast cancer models. Since the therapeutic effects of the administration of a single type of polyphenol might be limited because of the reduced bioavailability of these drugs, investigations on combination of several polyphenols or polyphenols with conventional therapy will also be discussed. In addition, we present recent data focusing on clinical trials with polyphenols and new approaches with nanoparticles in breast cancer. Besides the clinical and translational findings this review systematically summarizes our current knowledge about the molecular mechanisms of anti-cancer effects of polyphenols, which are related to apoptosis, cell cycle regulation, plasma membrane receptors, signaling pathways and epigenetic mechanisms. At the same time the effects of polyphenols on primary tumor, metastasis and angiogenesis in breast cancer are discussed. The increasing enthusiasm regarding the combination of polyphenols and conventional therapy in breast cancer might lead to additional efforts to motivate further research in this field. Full article

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Novel 3-Amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine Derivatives with Anticancer Activity: Synthesis and QSAR Study

by Aneta Pogorzelska, Jarosław Sławiński, Kamil Brożewicz, Szymon Ulenberg and Tomasz Bączek

Molecules 2015, 20(12), 21960-21970; https://doi.org/10.3390/molecules201219821 - 9 Dec 2015

Cited by 10 | Viewed by 5600

Abstract

A series of new 3-amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives 5a–j have been synthesized and evaluated in vitro for their antiproliferative activity at the U.S. National Cancer Institute. The most active compound 5h showed significant cytotoxic effects against ovarian (OVCAR-3) and breast (MDA-MB-468) [...] Read more.

A series of new 3-amino-6-chloro-7-(azol-2 or 5-yl)-1,1-dioxo-1,4,2-benzodithiazine derivatives 5a–j have been synthesized and evaluated in vitro for their antiproliferative activity at the U.S. National Cancer Institute. The most active compound 5h showed significant cytotoxic effects against ovarian (OVCAR-3) and breast (MDA-MB-468) cancer (10% and 47% cancer cell death, respectively) as well as a good selectivity toward prostate (DU-145), colon (SW-620) and renal (TK-10) cancer cell lines. To obtain a deeper insight into the structure-activity relationships of the new compounds 5a–j QSAR studies have been applied. Theoretical calculations allowed the identification of molecular descriptors belonging to the RDF (RDF055p and RDF145m in the MOLT-4 and UO-31 QSAR models, respectively) and 3D-MorSE (Mor32m and Mor16e for MOLT-4 and UO-31 QSAR models) descriptor classes. Based on these data, QSAR models with good robustness and predictive ability have been obtained. Full article

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Open AccessArticle

Anticancer and Antibacterial Activity Studies of Gold(I)-Alkynyl Chromones

by Paweł Hikisz, Łukasz Szczupak, Aneta Koceva-Chyła, Adam Guśpiel, Luciano Oehninger, Ingo Ott, Bruno Therrien, Jolanta Solecka and Konrad Kowalski

Molecules 2015, 20(11), 19699-19718; https://doi.org/10.3390/molecules201119647 - 30 Oct 2015

Cited by 46 | Viewed by 8847

Abstract

Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human [...] Read more.

Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain. Full article

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Open AccessArticle

Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit

by Chunjiang Wu, Min Wang, Qidong Tang, Rong Luo, Le Chen, Pengwu Zheng and Wufu Zhu

Molecules 2015, 20(10), 19361-19371; https://doi.org/10.3390/molecules201019361 - 23 Oct 2015

Cited by 39 | Viewed by 9003

Abstract

Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by ¹H-NMR, ¹³C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 [...] Read more.

Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by ¹H-NMR, ¹³C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 cancer cell lines. Some of the compounds showed moderate cytotoxic activity, especially compounds 1-(2,4-difluorophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6c) and 1-(4-bromophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6f) with the IC₅₀ values against four cancer cell lines ranging from 16.54 ± 1.22 to 63.92 ± 1.81 μM, respectively. Inhibitory rates against vascular endothelial growth factor receptor-2 (VEGFR2/KDR) kinase at 10 μM of target compounds were further carried out in this paper in order to investigate the target of these compounds. Structure-activity relationships (SARs) and docking studies indicated that the sulfonylurea unit was important to these kinds of compounds. None of the substitutions in the phenoxy group and small halogen atoms such as 2,4-difluoro substitution of the aryl group contributed to the activity. The results suggested that sulfonylurea sorafenib analogs are worthy of further study. Full article

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Synthesis and Evaluation of New Pyrazoline Derivatives as Potential Anticancer Agents

by Muhammed Karabacak, Mehlika Dilek Altıntop, Halil İbrahim Çiftçi, Ryoko Koga, Masami Otsuka, Mikako Fujita and Ahmet Özdemir

Molecules 2015, 20(10), 19066-19084; https://doi.org/10.3390/molecules201019066 - 20 Oct 2015

Cited by 82 | Viewed by 10426

Abstract

New pyrazoline derivatives were synthesized and evaluated for their cytotoxic effects on AsPC-1 human pancreatic adenocarcinoma, U87 and U251 human glioblastoma cell lines. 1-[((5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (11) was found to be the most effective anticancer agent against AsPC-1 and U251 cell lines, with [...] Read more.

New pyrazoline derivatives were synthesized and evaluated for their cytotoxic effects on AsPC-1 human pancreatic adenocarcinoma, U87 and U251 human glioblastoma cell lines. 1-[((5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (11) was found to be the most effective anticancer agent against AsPC-1 and U251 cell lines, with IC₅₀ values of 16.8 µM and 11.9 µM, respectively. Tumor selectivity of compound 11 was clearly seen between Jurkat human leukemic T-cell line and human peripheral blood mononuclear cells (PBMC). Due to its promising anticancer activity, compound 11 was chosen for apoptosis/necrosis evaluation and DNA-cleavage analysis in U251 cells. Compound 11-treated U251 cells exhibited apoptotic phenotype at low concentration (1.5 µM). DNA-cleaving efficiency of this ligand was more significant than cisplatin and was clearly enhanced by Fe(II)-H₂O₂-ascorbic acid systems. This result pointed out the relationship between the DNA cleavage and the cell death. Full article

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Open AccessArticle

Lead Optimization of 2-Cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides for Targeting the HER-2 Overexpressed Breast Cancer Cell Line SKBr-3

by Mashooq A. Bhat, Abdullah Al-Dhfyan, Ahmed M. Naglah, Azmat Ali Khan and Mohamed A. Al-Omar

Molecules 2015, 20(10), 18246-18263; https://doi.org/10.3390/molecules201018246 - 7 Oct 2015

Cited by 11 | Viewed by 6078

Abstract

Lead derivatives of 2-cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides 1–18 were synthesized, characterized and evaluated in vitro against HER-2 overexpressed breast cancer cell line SKBr-3. All the compounds showed activity against HER-2 overexpressed SKBr-3 cells with IC₅₀ = 17.44 ± [...] Read more.

Lead derivatives of 2-cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides 1–18 were synthesized, characterized and evaluated in vitro against HER-2 overexpressed breast cancer cell line SKBr-3. All the compounds showed activity against HER-2 overexpressed SKBr-3 cells with IC₅₀ = 17.44 ± 0.01 µM to 53.29 ± 0.33 µM. (2Z)-2-(3-Hydroxybenzylidene)-N-(3-methoxyphenyl)hydrazinecarbothioamide (12, IC₅₀ = 17.44 ± 0.01 µM) was found to be most potent compound of this series targeting HER-2 overexpressed breast cancer cells compared to the standard drug 5-fluorouracil (5-FU) (IC₅₀ = 38.58 ± 0.04 µM). Compound 12 inhibited the cellular proliferation via DNA degradation. Full article

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Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel 5H-Chromenopyridines as Potential Anti-Cancer Agents

by Souvik Banerjee, Jin Wang, Susan Pfeffer, Dejian Ma, Lawrence M. Pfeffer, Shivaputra A. Patil, Wei Li and Duane D. Miller

Molecules 2015, 20(9), 17152-17165; https://doi.org/10.3390/molecules200917152 - 17 Sep 2015

Cited by 30 | Viewed by 6868

Abstract

A novel series of 5H-chromenopyridines was identified as anticancer agents in our continuing effort to discover and develop new small molecule anti-proliferative agents. Based on our initial lead SP-6-27 compound, we designed and synthesized novel tricyclic 5H-thiochromenopyridine and 5 [...] Read more.

A novel series of 5H-chromenopyridines was identified as anticancer agents in our continuing effort to discover and develop new small molecule anti-proliferative agents. Based on our initial lead SP-6-27 compound, we designed and synthesized novel tricyclic 5H-thiochromenopyridine and 5H-chromenopyridine analogs to evaluate the impact of an additional ring, as well as conformational flexibility on cytotoxic activity against human melanoma and glioma cell lines. All of the 5H-thiochromenopyridines have been achieved in good yields (89%–93%) using a single-step, three-component cyclization without the need for purification. The 5H-chromenopyridine analog of the potent 5H-thiochromenopyride was obtained in a good yield upon purification. All newly-prepared 5H-thiochromenopyridines showed good to moderate cytotoxicity against three melanoma and two glioma cell lines (3–15 μM). However, the 5H-chromenopyridine analogue that we prepared in our laboratory lost cytotoxic activity. The moderate cytotoxic activity of 5H-thiochromenopyridines shows the promise of developing chromenopyridines as potential anticancer agents. Full article

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Open AccessArticle

Synthesis, Spectral Analysis and Preliminary in Vitro Evaluation of Some Tetrapyrrolic Complexes with 3d Metal Ions

by Radu Socoteanu, Gina Manda, Rica Boscencu, Georgiana Vasiliu and Anabela Sousa Oliveira

Molecules 2015, 20(9), 15488-15499; https://doi.org/10.3390/molecules200915488 - 26 Aug 2015

Cited by 13 | Viewed by 5526

Abstract

In this paper, two tetrapyrrolic complexes, Zn(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin and Cu(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin were synthesized, and characterized from a spectral and biological point of view. The study provided data concerning the behavior of identical external substituents vs. two different core insertions. Some of the properties of the [...] Read more.

In this paper, two tetrapyrrolic complexes, Zn(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin and Cu(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin were synthesized, and characterized from a spectral and biological point of view. The study provided data concerning the behavior of identical external substituents vs. two different core insertions. Some of the properties of the proposed tetrapyrrolic structures were highlighted, having photodynamic therapy of cancer as a targeted biomedical application. Elemental analysis, NMR, FTIR and UV-Vis data in various solvents were provided. A preliminary in vitro study on normal and cancer cultured cells was carried out for biocompatibility assessment in dark conditions. The preliminary in vitro study performed on human peripheral mononuclear cells exposed to tetrapyrrolic compounds (2 µM) showed that the proposed compounds had a convenient cytotoxic profile on human normal peripheral blood mononuclear cells under dark conditions. Meanwhile, the investigated compounds reduced the number of metabolically active breast tumor MCF-7 cells, with the exception of Zn(II) complex-containing a symmetrical ligand. Accordingly, preliminary in vitro data suggest that the proposed tetrapyrrolic compounds are good candidates for PDT, as they limit tumor expansion even under dark conditions, whilst sparing normal cells. Full article

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Open AccessArticle

Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation

by Ya-Jun Li, Cai-Yi Wang, Man-Yi Ye, Gui-Yang Yao and Heng-Shan Wang

Molecules 2015, 20(8), 14791-14809; https://doi.org/10.3390/molecules200814791 - 13 Aug 2015

Cited by 34 | Viewed by 6981

Abstract

A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives [...] Read more.

A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC₅₀ value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety. Full article

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Open AccessArticle

CAPE Analogs Induce Growth Arrest and Apoptosis in Breast Cancer Cells

by Annie-Pier Beauregard, Jason Harquail, Grégoire Lassalle-Claux, Mehdi Belbraouet, Jacques Jean-Francois, Mohamed Touaibia and Gilles A. Robichaud

Molecules 2015, 20(7), 12576-12589; https://doi.org/10.3390/molecules200712576 - 10 Jul 2015

Cited by 32 | Viewed by 7514

Abstract

Breast cancer is the second leading cause of death amongst women worldwide. As a result, many have turned their attention to new alternative approaches to treat this disease. Caffeic acid phenylethyl ester (CAPE), a well-known active compound from bee propolis, has been previously [...] Read more.

Breast cancer is the second leading cause of death amongst women worldwide. As a result, many have turned their attention to new alternative approaches to treat this disease. Caffeic acid phenylethyl ester (CAPE), a well-known active compound from bee propolis, has been previously identified as a strong antioxidant, anti-inflammatory, antiviral and anticancer molecule. In fact, CAPE is well documented as inducing cell death by inhibiting NFκB and by inducing pro-apoptotic pathways (i.e., p53). With the objective of developing stronger anticancer compounds, we studied 18 recently described CAPE derivatives for their ability to induce apoptosis in breast cancer cell lines. Five of the said compounds, including CAPE, were selected and subsequently characterised for their anticancer mechanism of action. We validated that CAPE is a potent inducer of caspase-dependent apoptosis. Interestingly, some newly synthesized CAPE derivatives also showed greater cell death activity than the lead CAPE structure. Similarly to CAPE, analog compounds elicited p53 activation. Interestingly, one compound in particular, analog 10, induced apoptosis in a p53-mutated cell line. These results suggest that our new CAPE analog compounds may display the capacity to induce breast cancer apoptosis in a p53-dependent and/or independent manner. These CAPE analogs could thus provide new therapeutic approaches for patients with varying genotypic signatures (such as p53 mutations) in a more specific and targeted fashion. Full article

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Open AccessArticle

Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity

by Krzysztof Szafrański and Jarosław Sławiński

Molecules 2015, 20(7), 12029-12044; https://doi.org/10.3390/molecules200712029 - 1 Jul 2015

Cited by 18 | Viewed by 6844

Abstract

A series of novel 4-substituted-N-(phenylcarbamoyl)-3-pyridinesulfonamides 11–27 have been synthesized by the reaction of 4-substituted pyridine-3-sulfonamides 2–10 with the appropriate aryl isocyanates in presence of potassium carbonate. The in vitro anticancer activity of compounds 11, 12, [...] Read more.

A series of novel 4-substituted-N-(phenylcarbamoyl)-3-pyridinesulfonamides 11–27 have been synthesized by the reaction of 4-substituted pyridine-3-sulfonamides 2–10 with the appropriate aryl isocyanates in presence of potassium carbonate. The in vitro anticancer activity of compounds 11, 12, 14–21 and 24–26 was evaluated at the U.S. National Cancer Institute and in light of the results, some structure-activity relationships were discussed. The most prominent compound, N-[(4-chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (21) has exhibited a good activity profile and selectivity toward the subpanels of leukemia, colon cancer and melanoma, with average GI₅₀ values ranging from 13.6 to 14.9 µM. Full article

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Open AccessArticle

Synthesis and Biological Evaluation of Lipophilic 1,4-Naphthoquinone Derivatives against Human Cancer Cell Lines

by Shao-Hung Wang, Chih-Yu Lo, Zhong-Heng Gwo, Hong-Jhih Lin, Lih-Geeng Chen, Cheng-Deng Kuo and Jin-Yi Wu

Molecules 2015, 20(7), 11994-12015; https://doi.org/10.3390/molecules200711994 - 30 Jun 2015

Cited by 38 | Viewed by 9113

Abstract

To examine the effect of hydrophobicity on the anticancer activity of 1,4-naphthoquinone derivatives, a series of compounds bearing a 2-O-alkyl-, 3-C-alkyl- or 2/3-N-morpholinoalkyl group were synthesized and evaluated for their anticancer activity against five human cancer cell [...] Read more.

To examine the effect of hydrophobicity on the anticancer activity of 1,4-naphthoquinone derivatives, a series of compounds bearing a 2-O-alkyl-, 3-C-alkyl- or 2/3-N-morpholinoalkyl group were synthesized and evaluated for their anticancer activity against five human cancer cell lines in vitro. The cytotoxicity of these derivatives was assayed against HT-29, SW480, HepG2, MCF-7 and HL-60 cells by the MTT assay. Among them, 2-hydroxy-3-farnesyl-1,4-naphthoquinone (11a) was found to be the most cytotoxic against these cell lines. Our results showed that the effectiveness of compound 11a may be attributed to its suppression of the survival of HT-29. Secondly, in the Hoechst 33258 staining test, compound 11a-treated cells exhibited nuclear condensation typical of apoptosis. Additionally, cell cycle analysis by flow cytometry indicated that compound 11a arrested HT-29 cells in the S phase. Furthermore, cell death detected by Annexin V-FITC/propidium iodide staining showed that compound 11a efficiently induced apoptosis of HT-29 in a concentration-dependent manner. Taken together, compound 11a effectively inhibits colon cancer cell proliferation and may be a potent anticancer agent. Full article

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Open AccessArticle

Induction of Mitochondrial Dependent Apoptosis in Human Leukemia K562 Cells by Meconopsis integrifolia: A Species from Traditional Tibetan Medicine

by Jianping Fan, Pan Wang, Xiaobing Wang, Wei Tang, Chunliang Liu, Yaqin Wang, Wenjuan Yuan, Lulu Kong and Quanhong Liu

Molecules 2015, 20(7), 11981-11993; https://doi.org/10.3390/molecules200711981 - 30 Jun 2015

Cited by 19 | Viewed by 7834

Abstract

Objectives: Meconopsis integrifolia (M. integrifolia) is one of the most popular members in Traditional Tibetan Medicine. This study aimed to investigate the anticancer effect of M. integrifolia and to detect the underlying mechanisms of these effects. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide [...] Read more.

Objectives: Meconopsis integrifolia (M. integrifolia) is one of the most popular members in Traditional Tibetan Medicine. This study aimed to investigate the anticancer effect of M. integrifolia and to detect the underlying mechanisms of these effects. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and trypan blue assay were used to evaluate the cytotoxicity of M. integrifolia. Changes in cell nuclear morphology and reactive oxygen species (ROS) level were observed by fluorescent microscopy. Apoptosis ratio, DNA damage and mitochondrial membrane potential (MMP) loss were analyzed by flow cytometry. Western blotting assay was adopted to detect the proteins related to apoptosis. Immunoﬂuorescence was used to observe the release of cytochrome C. Results: The obtained data revealed that M. integrifolia could significantly inhibit K562 cell viability, mainly by targeting apoptosis induction and cell cycle arrest in G2/M phase. Collapse in cell morphology, chromatin condensation, DNA damage and ROS accumulation were observed. Further mechanism detection revealed that mitochondrion might be a key factor in M. integrifolia-induced apoptosis. Conclusions: M. integrifolia could induce mitochondria mediated apoptosis and cell cycle arrest in G2/M phase with little damage to normal cells, suggesting that M. integrifolia might be a potential and efficient anticancer agent that deserves further investigation. Full article

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Open AccessArticle

A Selective G-Quadruplex DNA-Stabilizing Ligand Based on a Cyclic Naphthalene Diimide Derivative

by Md. Monirul Islam, Satoshi Fujii, Shinobu Sato, Tatsuo Okauchi and Shigeori Takenaka

Molecules 2015, 20(6), 10963-10979; https://doi.org/10.3390/molecules200610963 - 12 Jun 2015

Cited by 35 | Viewed by 8949

Abstract

A cyclic naphthalene diimide (cyclic NDI, 1), carrying a benzene moiety as linker chain, was synthesized and its interaction with G-quadruplex DNAs of a-core and a-coreTT as a human telomeric DNA, c-kit and c-myc as DNA sequence at promoter region, or thrombin-binding [...] Read more.

A cyclic naphthalene diimide (cyclic NDI, 1), carrying a benzene moiety as linker chain, was synthesized and its interaction with G-quadruplex DNAs of a-core and a-coreTT as a human telomeric DNA, c-kit and c-myc as DNA sequence at promoter region, or thrombin-binding aptamer (TBA) studied based on UV-VIS and circular dichroism (CD) spectroscopic techniques, thermal melting temperature measurement, and FRET-melting assay. The circular dichroism spectra showed that 1 induced the formation of different types of G-quadruplex DNA structure. Compound 1 bound to these G-quadruplexes with affinities in the range of 10⁶–10⁷ M⁻¹ order and a 2:1 stoichiometry. Compound 1 showed 270-fold higher selectivity for a-core than dsDNA with a preferable a-core binding than a-coreTT, c-kit, c-myc and TBA in the presence of K⁺, which is supported by thermal melting studies. The FRET-melting assay also showed that 1 bound preferentially to human telomeric DNA. Compound 1 showed potent inhibition against telomerase activity with an IC₅₀ value of 0.9 μM and preferable binding to G-quadruplexes DNA than our previously published cyclic NDI derivative 3 carrying a benzene moiety as longer linker chain. Full article

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Open AccessArticle

Optimization of Purification, Identification and Evaluation of the in Vitro Antitumor Activity of Polyphenols from Pinus Koraiensis Pinecones

by Juanjuan Yi, Zhenyu Wang, Haina Bai, Xiaojin Yu, Jing Jing and Lili Zuo

Molecules 2015, 20(6), 10450-10467; https://doi.org/10.3390/molecules200610450 - 5 Jun 2015

Cited by 42 | Viewed by 7733

Abstract

In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP [...] Read more.

In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93 ± 0.14% (n = 3), which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line), A549 (human lung cancer cell line), SH-SY5Y (human neuroblastoma cell line), LOVO (human colon cancer stem cell line), MCF-7 (human breast cancer cell line), HeLa (human cervical cancer line), and HT29 (human colon cancer line), were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC₅₀ value of 0.317 ± 0.0476 mg/mL. Finally, Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS) was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstrate that Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods. Full article

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Open AccessCommunication

Synthesis and Biological Evaluation of Novel Water-Soluble Poly-(ethylene glycol)-10-hydroxycamptothecin Conjugates

by Na Guo, Du Jiang, Luyao Wang, Xing You, Yu-Ou Teng and Peng Yu

Molecules 2015, 20(5), 9393-9404; https://doi.org/10.3390/molecules20059393 - 21 May 2015

Cited by 4 | Viewed by 8837

Abstract

In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of [...] Read more.

In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 °C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2–5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f) exhibited controlled release of HCPT and excellent antitumor in vitro activity. Full article

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Open AccessArticle

Novel All Trans-Retinoic Acid Derivatives: Cytotoxicity, Inhibition of Cell Cycle Progression and Induction of Apoptosis in Human Cancer Cell Lines

by Ebtesam Saad Al-Sheddi, Mai Mohammad Al-Oqail, Quaiser Saquib, Maqsood Ahmed Siddiqui, Javed Musarrat, Abdulaziz Ali Al-Khedhairy and Nida Nayyar Farshori

Molecules 2015, 20(5), 8181-8197; https://doi.org/10.3390/molecules20058181 - 7 May 2015

Cited by 23 | Viewed by 7943

Abstract

Owing to the pharmacological potential of ATRA (all trans-retinoic acid), a series of retinamides and a 1-(retinoyl)-1,3-dicyclohexylurea compound were prepared by reacting ATRA with long chain alkyl or alkenyl fatty amines by using a 4-demethylaminopyridine (DMAP)-catalyzed N,N¢-dicyclohexylcarbodiimide (DCC) coupling. The successful synthesis [...] Read more.

Owing to the pharmacological potential of ATRA (all trans-retinoic acid), a series of retinamides and a 1-(retinoyl)-1,3-dicyclohexylurea compound were prepared by reacting ATRA with long chain alkyl or alkenyl fatty amines by using a 4-demethylaminopyridine (DMAP)-catalyzed N,N¢-dicyclohexylcarbodiimide (DCC) coupling. The successful synthesis of the target compounds was demonstrated using a range of spectroscopic techniques. The cytotoxicity of the compounds was measured along with their ability to induce cell cycle arrest and apoptosis in human cancer cell lines MCF-7 (breast cancer) and HepG2 (liver cancer) and normal human cell line HEK293 (embryonic kidney). The results of cytotoxicity and flow cytometry data showed that the compounds had a moderate to strong effect against MCF-7 and HepG2 cells and were less toxic to HEK293 cells. N-oleyl-retinamide was found to be the most potent anticancer agent and was more effective against MCF-7 cells than HepG2 cells. Full article

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Open AccessArticle

5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors

by Pu Xiang, Hui Jie, Yang Zhou, Bo Yang, Hui-Juan Wang, Jing Hu, Jian Hu, Sheng-Yong Yang and Ying-Lan Zhao

Molecules 2015, 20(5), 7620-7636; https://doi.org/10.3390/molecules20057620 - 27 Apr 2015

Cited by 11 | Viewed by 7736

Abstract

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC₅₀ value of 1.2 μM against [...] Read more.

A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC₅₀ value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization. Full article

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Open AccessReview

A Survey of Marine Natural Compounds and Their Derivatives with Anti-Cancer Activity Reported in 2012

by Wamtinga Richard Sawadogo, Rainatou Boly, Claudia Cerella, Marie Hélène Teiten, Mario Dicato and Marc Diederich

Molecules 2015, 20(4), 7097-7142; https://doi.org/10.3390/molecules20047097 - 20 Apr 2015

Cited by 43 | Viewed by 10798

Abstract

Although considerable effort and progress has been made in the search for new anticancer drugs and treatments in the last several decades, cancer remains a major public health problem and one of the major causes of death worldwide. Many sources, including plants, animals, [...] Read more.

Although considerable effort and progress has been made in the search for new anticancer drugs and treatments in the last several decades, cancer remains a major public health problem and one of the major causes of death worldwide. Many sources, including plants, animals, and minerals, are of interest in cancer research because of the possibility of identifying novel molecular therapeutics. Moreover, structure-activity-relationship (SAR) investigations have become a common way to develop naturally derived or semi-synthetic molecular analogues with improved efficacy and decreased toxicity. In 2012, approximately 138 molecules from marine sources, including isolated compounds and their associated analogues, were shown to be promising anticancer drugs. Among these, 62% are novel compounds. In this report, we review the marine compounds identified in 2012 that may serve as novel anticancer drugs. Full article

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Open AccessArticle

Synthesis and Pharmacophore Modelling of 2,6,9-Trisubstituted Purine Derivatives and Their Potential Role as Apoptosis-Inducing Agents in Cancer Cell Lines

by Jeannette Calderón-Arancibia, Christian Espinosa-Bustos, Álvaro Cañete-Molina, Ricardo A. Tapia, Mario Faúndez, Maria Jose Torres, Adam Aguirre, Margot Paulino and Cristian O. Salas

Molecules 2015, 20(4), 6808-6826; https://doi.org/10.3390/molecules20046808 - 15 Apr 2015

Cited by 34 | Viewed by 8109

Abstract

A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine [...] Read more.

A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds. Full article

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Open AccessArticle

QSAR-Assisted Virtual Screening of Lead-Like Molecules from Marine and Microbial Natural Sources for Antitumor and Antibiotic Drug Discovery

by Florbela Pereira, Diogo A. R. S. Latino and Susana P. Gaudêncio

Molecules 2015, 20(3), 4848-4873; https://doi.org/10.3390/molecules20034848 - 17 Mar 2015

Cited by 27 | Viewed by 8874

Abstract

A Quantitative Structure-Activity Relationship (QSAR) approach for classification was used for the prediction of compounds as active/inactive relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1746 compounds from PubChem with empirical CDK descriptors and semi-empirical quantum-chemical descriptors. [...] Read more.

A Quantitative Structure-Activity Relationship (QSAR) approach for classification was used for the prediction of compounds as active/inactive relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1746 compounds from PubChem with empirical CDK descriptors and semi-empirical quantum-chemical descriptors. A data set of 183 active pharmaceutical ingredients was additionally used for the external validation of the best models. The best classification models for antibiotic and antitumor activities were used to screen a data set of marine and microbial natural products from the AntiMarin database—25 and four lead compounds for antibiotic and antitumor drug design were proposed, respectively. The present work enables the presentation of a new set of possible lead like bioactive compounds and corroborates the results of our previous investigations. By other side it is shown the usefulness of quantum-chemical descriptors in the discrimination of biologically active and inactive compounds. None of the compounds suggested by our approach have assigned non-antibiotic and non-antitumor activities in the AntiMarin database and almost all were lately reported as being active in the literature. Full article

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Open AccessReview

Development of Advanced Macrosphelides: Potent Anticancer Agents

by Seung-Mann Paek

Molecules 2015, 20(3), 4430-4449; https://doi.org/10.3390/molecules20034430 - 10 Mar 2015

Cited by 8 | Viewed by 5756

Abstract

Synthetic approaches to macrosphelide derivatives, based on medicinal chemistry, are summarized. This review contains conventional medicinal chemistry approaches, combinatorial chemistry, fluorous tagging techniques and affinity chromatography preparation. In addition, advances in their apoptosis-inducing activities are also included. Full article

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Open AccessArticle

Pharmacokinetics and Tissue Distribution Study of Caudatin in Normal and Diethylnitrosamine-Induced Hepatocellular Carcinoma Model Rats

by Yunru Peng and Yongfang Ding

Molecules 2015, 20(3), 4225-4237; https://doi.org/10.3390/molecules20034225 - 5 Mar 2015

Cited by 18 | Viewed by 6777

Abstract

Caudatin is a potential antitumor agent isolated from the traditional Chinese medicine “baishouwu”, which was the root tuber of Cynanchum auriculatum Royle ex Wight. In our previous studies, caudatin showed selectivity on human hepatoma cell line SMMC7721 among several different tumor [...] Read more.

Caudatin is a potential antitumor agent isolated from the traditional Chinese medicine “baishouwu”, which was the root tuber of Cynanchum auriculatum Royle ex Wight. In our previous studies, caudatin showed selectivity on human hepatoma cell line SMMC7721 among several different tumor cell lines, and further in vivo tests validated the inhibitory action of caudatin against hepatic cancer using an H₂₂ solid tumor model in mice, but to our knowledge, the biopharmaceutical properties of caudatin are largely unknown. In this study, a simple, rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of caudatin in rat plasma and tissues, which kept the run time to detect one sample within 4 min, was developed and validated. Pharmacokinetics and tissue distribution studies of caudatin in conventional rats and hepatocellular carcinoma (HCC) model rats were then conducted for the first time. Statistically significant differences were observed between conventional rats and diethylnitrosamine (DEN)-induced HCC rats with respect to pharmacokinetic parameters, including maximum concentration (C_max), time to reach C_max (T_max), half-life (t_1/2), area under the concentration-time curve (AUC_0-t, AUC_0-∞), mean residence time (MRT_0-t and MRT_0-∞), and oral clearance (CL/F). Increased exposures of caudatin were found in the plasma and livers of HCC model rats, which would be helpful for a better understanding of pharmacological effect of caudatin in treating HCC disease. Full article

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Open AccessReview

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

by Madhusoodanan Mottamal, Shilong Zheng, Tien L. Huang and Guangdi Wang

Molecules 2015, 20(3), 3898-3941; https://doi.org/10.3390/molecules20033898 - 2 Mar 2015

Cited by 594 | Viewed by 22628

Abstract

Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing [...] Read more.

Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility. Full article

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Open AccessReview

Targeting Carbonic Anhydrase IX Activity and Expression

by Brian P. Mahon, Melissa A. Pinard and Robert McKenna

Molecules 2015, 20(2), 2323-2348; https://doi.org/10.3390/molecules20022323 - 30 Jan 2015

Cited by 103 | Viewed by 14154

Abstract

Metastatic tumors are often hypoxic exhibiting a decrease in extracellular pH (~6.5) due to a metabolic transition described by the Warburg Effect. This shift in tumor cell metabolism alters the tumor milieu inducing tumor cell proliferation, angiogenesis, cell motility, invasiveness, and often resistance [...] Read more.

Metastatic tumors are often hypoxic exhibiting a decrease in extracellular pH (~6.5) due to a metabolic transition described by the Warburg Effect. This shift in tumor cell metabolism alters the tumor milieu inducing tumor cell proliferation, angiogenesis, cell motility, invasiveness, and often resistance to common anti-cancer treatments; hence hindering treatment of aggressive cancers. As a result, tumors exhibiting this phenotype are directly associated with poor prognosis and decreased survival rates in cancer patients. A key component to this tumor microenvironment is carbonic anhydrase IX (CA IX). Knockdown of CA IX expression or inhibition of its activity has been shown to reduce primary tumor growth, tumor proliferation, and also decrease tumor resistance to conventional anti-cancer therapies. As such several approaches have been taken to target CA IX in tumors via small-molecule, anti-body, and RNAi delivery systems. Here we will review recent developments that have exploited these approaches and provide our thoughts for future directions of CA IX targeting for the treatment of cancer. Full article

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Open AccessCommunication

Synthesis and Biological Evaluation of Novel 6-Hydroxy-benzo[d][1,3]oxathiol-2-one Schiff Bases as Potential Anticancer Agents

by Eliza De Lucas Chazin, Paola De Souza Sanches, Eric Brazil Lindgren, Walcimar Trindade Vellasco Júnior, Laine Celestino Pinto, Rommel Mario Rodríguez Burbano, Julliane Diniz Yoneda, Kátia Zaccur Leal, Claudia Regina Brandão Gomes, James Lewis Wardell, Solange Maria Silva Veloso Wardell, Raquel Carvalho Montenegro and Thatyana Rocha Alves Vasconcelos

Molecules 2015, 20(2), 1968-1983; https://doi.org/10.3390/molecules20021968 - 27 Jan 2015

Cited by 19 | Viewed by 7734

Abstract

With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The [...] Read more.

With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a–r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (¹H and ¹³C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC₅₀ values lower than 5 μM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer. Full article

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Open AccessArticle

Deoxypodophyllotoxin Induces G2/M Cell Cycle Arrest and Apoptosis in SGC-7901 Cells and Inhibits Tumor Growth in Vivo

by Yu-Rong Wang, Yuan Xu, Zhen-Zhou Jiang, Mounia Guerram, Bin Wang, Xiong Zhu and Lu-Yong Zhang

Molecules 2015, 20(1), 1661-1675; https://doi.org/10.3390/molecules20011661 - 20 Jan 2015

Cited by 47 | Viewed by 10731

Abstract

Deoxypodophyllotoxin (DPT), a natural microtubule destabilizer, was isolated from Anthriscus sylvestris, and a few studies have reported its anti-cancer effect. However, the in vivo antitumor efficacy of DPT is currently indeterminate. In this study, we investigated the anti-gastric cancer effects of DPT [...] Read more.

Deoxypodophyllotoxin (DPT), a natural microtubule destabilizer, was isolated from Anthriscus sylvestris, and a few studies have reported its anti-cancer effect. However, the in vivo antitumor efficacy of DPT is currently indeterminate. In this study, we investigated the anti-gastric cancer effects of DPT both in vitro and in vivo. Our data showed that DPT inhibited cancer cell proliferation and induced G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. In addition, DPT caused cyclin B1, Cdc2 and Cdc25C to accumulate, decreased the expression of Bcl-2 and activated caspase-3 and PARP, suggesting that caspase-mediated pathways were involved in DPT-induced apoptosis. Animal studies revealed that DPT significantly inhibited tumor growth and decreased microvessel density (MVD) in a xenograft model of gastric cancer. Taken together, our findings provide a framework for further exploration of DPT as a novel chemotherapeutic for human gastric cancer. Full article

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Open AccessArticle

Kinase Inhibitor Profile for Human Nek1, Nek6, and Nek7 and Analysis of the Structural Basis for Inhibitor Specificity

by Eduardo Cruz Moraes, Gabriela Vaz Meirelles, Rodrigo Vargas Honorato, Tatiana De Arruda Campos Brasil De Souza, Edmarcia Elisa De Souza, Mario Tyago Murakami, Paulo Sergio Lopes De Oliveira and Jörg Kobarg

Molecules 2015, 20(1), 1176-1191; https://doi.org/10.3390/molecules20011176 - 13 Jan 2015

Cited by 25 | Viewed by 9712

Abstract

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and [...] Read more.

Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant T_m shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt. Each one of these compounds was also validated by reducing the kinases activity by at least 25%. The binding sites for these compounds were identified by in silico docking at the ATP-binding site of the respective hNeks. Potential inhibitors were first screened by thermal shift assays, had their efficiency tested by a kinase assay, and were finally analyzed by molecular docking. Our findings corroborate the idea of ATP-competitive inhibition for hNek1 and hNek6 and suggest a novel non-competitive inhibition for hNek7 in regard to GSK-3 Inhibitor XIII. Our results demonstrate that our approach is useful for finding promising general and specific hNekscandidate inhibitors, which may also function as scaffolds to design more potent and selective inhibitors. Full article

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Synthesis of Chromonylthiazolidines and Their Cytotoxicity to Human Cancer Cell Lines

by Hoang Le Tuan Anh, Nguyen Thi Cuc, Bui Huu Tai, Pham Hai Yen, Nguyen Xuan Nhiem, Do Thi Thao, Nguyen Hoai Nam, Chau Van Minh, Phan Van Kiem and Young Ho Kim

Molecules 2015, 20(1), 1151-1160; https://doi.org/10.3390/molecules20011151 - 12 Jan 2015

Cited by 27 | Viewed by 7151

Abstract

Nine new chromonylthiazolidine derivatives were successfully semi-synthesized from paeonol. All of the compounds, including starting materials, the intermediate compound and products, were evaluated for their cytotoxic effects toward eight human cancer cell lines. The synthesized chromonylthiazolidines displayed weak cytotoxic effects against the tested [...] Read more.

Nine new chromonylthiazolidine derivatives were successfully semi-synthesized from paeonol. All of the compounds, including starting materials, the intermediate compound and products, were evaluated for their cytotoxic effects toward eight human cancer cell lines. The synthesized chromonylthiazolidines displayed weak cytotoxic effects against the tested cancer cell lines, but selective cytotoxic effects were observed. Compounds 3a and 3b showed the most selective cytotoxic effects against human epidermoid carcinoma (IC₅₀ 44.1 ± 3.6 μg/mL) and breast cancer (IC₅₀ 32.8 ± 1.4 μg/mL) cell lines, respectively. The results suggest that chromoylthiazolidines are potential low-cost, and selective anticancer agents. Full article

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Open AccessReview

1-[2-(2-Methoxyphenylamino)ethylamino]-3-(naphthalene-1- yloxy)propan-2-ol May Be a Promising Anticancer Drug

by Tomoyuki Nishizaki, Takeshi Kanno, Ayako Tsuchiya, Yoshiko Kaku, Tadashi Shimizu and Akito Tanaka

Molecules 2014, 19(12), 21462-21472; https://doi.org/10.3390/molecules191221462 - 19 Dec 2014

Cited by 11 | Viewed by 8482

Abstract

We have originally synthesized the naftopidil analogue 1-[2-(2-methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol (HUHS 1015) as a new anticancer drug. HUHS1015 induces cell death in a wide variety of human cancer cell lines originated from malignant pleural mesothelioma, lung cancer, hepatoma, gastric cancer, colorectal cancer, bladder cancer, prostate [...] Read more.

We have originally synthesized the naftopidil analogue 1-[2-(2-methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol (HUHS 1015) as a new anticancer drug. HUHS1015 induces cell death in a wide variety of human cancer cell lines originated from malignant pleural mesothelioma, lung cancer, hepatoma, gastric cancer, colorectal cancer, bladder cancer, prostate cancer, and renal cancer. HUHS1015-induced cell death includes necrosis (necroptosis) and apoptosis, and the underlying mechanism differs depending upon cancer cell types. HUHS1015 effectively suppresses tumor growth in mice inoculated with NCI-H2052, MKN45, or CW2 cells, with a potential similar to or higher than that of currently used anticancer drugs. Here we show how HUHS1015 might offer brilliant hope for cancer therapy. Full article

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Open AccessReview

Anticancer Agents Targeted to Sirtuins

by Tomohiro Kozako, Takayoshi Suzuki, Makoto Yoshimitsu, Naomichi Arima, Shin-ichiro Honda and Shinji Soeda

Molecules 2014, 19(12), 20295-20313; https://doi.org/10.3390/molecules191220295 - 4 Dec 2014

Cited by 59 | Viewed by 10808

Abstract

Sirtuins are nicotinamide adenine dinucleotide⁺-dependent deacetylases of which there are seven isoforms (SIRT1–7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both [...] Read more.

Sirtuins are nicotinamide adenine dinucleotide⁺-dependent deacetylases of which there are seven isoforms (SIRT1–7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that modulate sirtuins, and these modulators have enabled a greater understanding of the biological function and molecular mechanisms of sirtuins. This review highlights the possibility of sirtuins, especially SIRT1 and SIRT2, for cancer therapy targets, and focuses on the therapeutic potential of sirtuin modulators both in cancer prevention and treatment. Full article

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Open AccessArticle

Discovery of Novel Small-Molecule Compounds with Selective Cytotoxicity for Burkitt’s Lymphoma Cells Using 3D Ligand-Based Virtual Screening

by Martina Gobec, Izidor Sosič, Boris Brus, Aleš Obreza, Stanislav Gobec and Irena Mlinarič-Raščan

Molecules 2014, 19(11), 19209-19219; https://doi.org/10.3390/molecules191119209 - 19 Nov 2014

Viewed by 7304

Abstract

We describe a ligand-based approach towards compounds with more specific targeting for Burkitt’s lymphoma. Using three-dimensional ligand-based similarity searches and a previously described hit compound, we have identified six compounds that are chemically different but with similar spatial conformations. Biological evaluation revealed that [...] Read more.

We describe a ligand-based approach towards compounds with more specific targeting for Burkitt’s lymphoma. Using three-dimensional ligand-based similarity searches and a previously described hit compound, we have identified six compounds that are chemically different but with similar spatial conformations. Biological evaluation revealed that one compound has better growth inhibition and improved selectivity towards Burkitt’s lymphoma cells than the query compound. However, initial mechanism-of-action studies show a different target profile in comparison with the previous hit compound, which does not involve the inhibition of the proteasome or the NFκB pathway. The data from this study provide a solid basis for further efforts in the search for selective agents against Burkitt’s lymphoma. Full article

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Open AccessArticle

Design, Synthesis, and Biological Evaluation of Artemisinin-Indoloquinoline Hybrids as Potent Antiproliferative Agents

by Li Wang, Marta Świtalska, Ning Wang, Zhen-Jun Du, Yuta Fukumoto, Nguyen Kim Diep, Ryo Kiguchi, Junzo Nokami, Joanna Wietrzyk and Tsutomu Inokuchi

Molecules 2014, 19(11), 19021-19035; https://doi.org/10.3390/molecules191119021 - 18 Nov 2014

Cited by 24 | Viewed by 9953

Abstract

A series of artemisinin-indoloquinoline hybrids were designed and synthesized in an attempt to develop potent and selective anti-tumor agents. Compounds 7a–7f, 8 and 9 were prepared and characterized. Their antiproliferative activities against MV4-11, HCT-116, A549, and BALB/3T3 cell lines in [...] Read more.

A series of artemisinin-indoloquinoline hybrids were designed and synthesized in an attempt to develop potent and selective anti-tumor agents. Compounds 7a–7f, 8 and 9 were prepared and characterized. Their antiproliferative activities against MV4-11, HCT-116, A549, and BALB/3T3 cell lines in vitro were tested. Nearly all of the tested compounds (7–9, except for compounds 7d and 7e against HCT-116) showed an increased antitumor activity against HCT-116 and A549 cell lines when compared to the dihydroartemisinin control. Especially for the artemisinin-indoloquinoline hybrid 8, with an 11-aminopropylamino-10H-indolo[3,2-b]quinoline substituent, the antiproliferative activity against the A549 cell line had improved more than ten times. The IC₅₀ value of hybrid 8 against A549 cell lines was decreased to 1.328 ± 0.586 μM, while dihydroartemisin showed IC₅₀ value of >20 µM in the same cell line. Thus, these results have proven that the strategy of introducing a planar basic fused aromatic moiety, such as the indoloquinoline skeleton, could improve the antiproliferative activity and selectivity towards cancer cell lines. Full article

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Study on the Cytotoxic Activity of Drimane Sesquiterpenes and Nordrimane Compounds against Cancer Cell Lines

by Ivan Montenegro, Giacomo Tomasoni, Claudia Bosio, Natalia Quiñones, Alejandro Madrid, Hector Carrasco, Andres Olea, Rolando Martinez, Mauricio Cuellar and Joan Villena

Molecules 2014, 19(11), 18993-19006; https://doi.org/10.3390/molecules191118993 - 18 Nov 2014

Cited by 30 | Viewed by 8060

Abstract

Twelve drimanes, including polygodial (1), isopolygodial (2), drimenol (3), confertifolin (4), and isodrimenin (5), were obtained from natural sources. Semi-synthetic derivatives 6–12 were obtained from 1 and 2, and cytotoxic [...] Read more.

Twelve drimanes, including polygodial (1), isopolygodial (2), drimenol (3), confertifolin (4), and isodrimenin (5), were obtained from natural sources. Semi-synthetic derivatives 6–12 were obtained from 1 and 2, and cytotoxic activity was evaluated in vitro against cancer cell lines (HT-29, MDA-MB231, DHF, MCF-7, PC-3, DU-145, and CoN). IC₅₀ values were determined at concentrations of 12.5–100 µM of each compound for 72 h. In addition, it was found that polygodial (1), 8, and 12 induced changes in mitochondrial membrane permeability in CoN, MCF-7, and PC-3 cells. Full article

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Open AccessArticle

Design and Synthesis of Isosteviol Triazole Conjugates for Cancer Therapy

by Ravil N. Khaybullin, Mei Zhang, Junjie Fu, Xiao Liang, Tammy Li, Alan R. Katritzky, Paul Okunieff and Xin Qi

Molecules 2014, 19(11), 18676-18689; https://doi.org/10.3390/molecules191118676 - 14 Nov 2014

Cited by 34 | Viewed by 8435

Abstract

One of the keys for successfully developing drugs against the broad spectrum of cancer cell types is structural diversity. In the current study, we focused on a family of isosteviol derivatives as potential novel antitumor agents. Isosteviol is a tetracyclic diterpenoid obtained by [...] Read more.

One of the keys for successfully developing drugs against the broad spectrum of cancer cell types is structural diversity. In the current study, we focused on a family of isosteviol derivatives as potential novel antitumor agents. Isosteviol is a tetracyclic diterpenoid obtained by acid hydrolysis of steviol glycoside extracts isolated from abundant Stevia rebaudiana plants. In this work, we have designed and synthesized a panel of isosteviol triazole conjugates using “click” chemistry methodology. Evaluation of these compounds against a series of cancer cell lines derived from primary and metastatic tumors demonstrated that these conjugates exhibit cytotoxic activities with IC₅₀ in the low μM range. In addition, their anti-proliferative activities are cancer cell type specific. Taken together, our studies underscore the importance of structural diversity in achieving cancer cell type specific drug development. Full article

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Synthesis and in Vitro Antitumor Activity of a Novel Series of 2-Pyrazoline Derivatives Bearing the 4-Aryloxy-7-chloroquinoline Fragment

by Alba Montoya, Jairo Quiroga, Rodrigo Abonia, Manuel Nogueras, Justo Cobo and Braulio Insuasty

Molecules 2014, 19(11), 18656-18675; https://doi.org/10.3390/molecules191118656 - 14 Nov 2014

Cited by 42 | Viewed by 6840

Abstract

A new series of NH-pyrazoline derivatives 6 was synthesized by cyclocondensation reaction of novel [(7-chloroquinolin-4-yl)oxy]chalcones 5 with hydrazine hydrate. The treatment of pyrazolines 6 with acetic anhydride or formic acid yielded the N-acetyl- or N-formylpyrazoline derivatives 7–8, [...] Read more.

A new series of NH-pyrazoline derivatives 6 was synthesized by cyclocondensation reaction of novel [(7-chloroquinolin-4-yl)oxy]chalcones 5 with hydrazine hydrate. The treatment of pyrazolines 6 with acetic anhydride or formic acid yielded the N-acetyl- or N-formylpyrazoline derivatives 7–8, respectively. These novel 2-pyrazoline derivatives 6–8 were evaluated by the U.S. National Cancer Institute (NCI). Compounds 7b,d,f and 8c,f showed remarkable antitumor activity against 58 cancer cell lines, with the most important GI₅₀ values from in vitro assays ranging from 0.48 to 1.66 μM. The 2-pyrazoline derivatives bearing the 4-aryloxy-7-chloroquinoline fragment are thus considered to be useful leads for the rational design of new antitumor agents. Full article

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Synthesis and Anti-Tumor Activity of Novel Aminomethylated Derivatives of Isoliquiritigenin

by Haoran Fu, Yuhang Zhang, Xiqing Wang, Yingzhi Han, Xiao Peng, Thomas Efferth and Yujie Fu

Molecules 2014, 19(11), 17715-17726; https://doi.org/10.3390/molecules191117715 - 31 Oct 2014

Cited by 6 | Viewed by 7750

Abstract

A series of new aminomethylated derivatives of isoliquiritigenin was synthesized. The structures of the compounds were confirmed by IR, MS, NMR, ¹³C-NMR and elemental analyses. Cytotoxic activities of these derivatives towards the human prostatic cell line PC-3, human mammary cancer cell line [...] Read more.

A series of new aminomethylated derivatives of isoliquiritigenin was synthesized. The structures of the compounds were confirmed by IR, MS, NMR, ¹³C-NMR and elemental analyses. Cytotoxic activities of these derivatives towards the human prostatic cell line PC-3, human mammary cancer cell line MCF-7 and human oophoroma cell line HO-8910 in vitro were tested. The IC₅₀ values showed cytotoxic activities of some of these new derivatives were relatively strong. Furthermore, tumor growth inhibition in vivo of aminomethylated derivatives of isoliquiritigenin 15 was superior to that of isoliquritigenin and reached inhibition rates of 71.68%. The detailed synthesis, spectroscopic data, biological and pharmacologicalactivities of the synthesized compounds were provided. Full article

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Structural Diversity of Copper(II) Complexes with N-(2-Pyridyl)Imidazolidin-2-Ones(Thiones) and Their in Vitro Antitumor Activity

by Łukasz Balewski, Franciszek Sączewski, Patrick J. Bednarski, Maria Gdaniec, Ewa Borys and Anna Makowska

Molecules 2014, 19(10), 17026-17051; https://doi.org/10.3390/molecules191017026 - 23 Oct 2014

Cited by 23 | Viewed by 8520

Abstract

Six series of structurally different mono- and binuclear copper(II) complexes 5–10 were obtained by reacting N-(2-pyridyl)imidazolidin-2-ones (1a–l), N,N'-bis(2-pyridyl)imidazolidin-2-ones (2a,b), N-acyl-N'(2-pyridyl)imidazolodin-2-ones (3a–j) and [...] Read more.

Six series of structurally different mono- and binuclear copper(II) complexes 5–10 were obtained by reacting N-(2-pyridyl)imidazolidin-2-ones (1a–l), N,N'-bis(2-pyridyl)imidazolidin-2-ones (2a,b), N-acyl-N'(2-pyridyl)imidazolodin-2-ones (3a–j) and N-(2-pyridyl)imidazolidine-2-thiones (4a–g) with copper(II) chloride at an ambient temperature. The coordination modes of the complexes obtained were established by elemental analysis, IR spectroscopic data and single crystal X-ray diffraction studies. The in vitro cytotoxic activities of both the free ligands and copper(II) complexes were evaluated using a crystal violet microtiter plate assay on five human tumor cell lines: LCLC-103H, A-427, SISO, RT-4 and DAN-G. The free ligands 1–4 at concentration attainable in cancer cells of 20 μM showed no meaningful cytotoxic effect with cell viability in the range of 88%–100%. The most potent copper(II) complex of 1-(6-ethoxy-2-pyridyl)imidazolidin-2-one (6b) exhibited selective cytotoxicity against A-427 lung cancer cell line, while the complexes of 1-(5-methyl-2-pyridyl)imidazolidine-2-thione (5h) and 1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione (5j) showed cytostatic effect against a whole panel of five human tumor cell lines. In conclusion, the only complexes that showed remarkably increased activity in comparison to the free ligands were those obtained from N-(2-pyridyl)imidazolidine-2-thiones 4c and 4e substituted with alkyl group at position 4 or 5 of pyridine ring. Full article

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Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines

by Zsolt Szakonyi, István Zupkó, Reijo Sillanpää and Ferenc Fülöp

Molecules 2014, 19(10), 15918-15937; https://doi.org/10.3390/molecules191015918 - 2 Oct 2014

Cited by 13 | Viewed by 8220

Abstract

Starting from pinane-, apopinane- and carane-based 1,3-amino alcohols obtained from monoterpene-based β-amino acids, a library of monoterpene-fused 2-imino-1,3-thiazines as main products and 2-thioxo-1,3-oxazines as side-products were prepared via two- or three-step syntheses. When thiourea adducts prepared from 1,3-amino alcohols and aryl isothiocyanates were [...] Read more.

Starting from pinane-, apopinane- and carane-based 1,3-amino alcohols obtained from monoterpene-based β-amino acids, a library of monoterpene-fused 2-imino-1,3-thiazines as main products and 2-thioxo-1,3-oxazines as side-products were prepared via two- or three-step syntheses. When thiourea adducts prepared from 1,3-amino alcohols and aryl isothiocyanates were reacted with CDI under mild conditions, O-imidazolylcarbonyl intermediates were isolated which could be transformed to the desired 1,3-thiazines under microwave conditions. 1,3-Thiazines and 2-thioxo-1,3-oxazine side-products could also be prepared in one-step reactions through the application of CDI and microwave irradiation. The ring-closure process was extended to cycloalkane-based γ-hydroxythioureas. The carane- and apopinane-based derivatives exhibited marked antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, A2780, MCF7 and A431). Full article

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Biological Evaluation of the Activity of Some Benzimidazole-4,7-dione Derivatives

by Katarzyna Błaszczak-Świątkiewicz and Elżbieta Mikiciuk-Olasik

Molecules 2014, 19(10), 15361-15373; https://doi.org/10.3390/molecules191015361 - 26 Sep 2014

Cited by 5 | Viewed by 6443

Abstract

The study presented here is a follow up of the authors’ interest in the approach to selective and cytotoxic bioreductive anticancer prodrugs. The current work is devoted to explore both the biological activity of some previously obtained compounds and the search for an [...] Read more.

The study presented here is a follow up of the authors’ interest in the approach to selective and cytotoxic bioreductive anticancer prodrugs. The current work is devoted to explore both the biological activity of some previously obtained compounds and the search for an explanation of their target(s) in hypoxic pathways. In this work the biological activity of some benzimidazole-4,7-diones was evaluated. These compounds were examined as potential bioreductive agents specific for the hypoxic environment found in tumor cells. The main aim was concerned with establishing their cytotoxic properties by using proliferation, apoptosis and DNA destruction tests on selected tumor cells. Their cytotoxic effects on two tumor cell lines (human lung adenocarcinoma A549 cells line and human malignant melanoma WM115) was compared by means of a WST-1 test. Next, the mode of cytotoxicity behind the selected tumor cells’ death was determined by the caspase 3/7 test. The last point referred to the DNA destruction of A549 and WM115 cells and the in situ DNA Assay Kit test was applied. The cytotoxic tests confirmed their activity against the tumor cells and target hypoxia (compounds 2b, 2a, 2d). The screening test of the caspase-dependent apoptosis proved that the exposure of the tested tumor cells in hypoxia to these benzimidazole-4,7-diones promoted the apoptotic cell death. Additionally, the DNA damage test established that benzimidazole-4,7-diones can be potential hypoxia-selective agents for tumor cells, especially compound 2b. All results classify the tested benzimidazole-4,7-diones as promising, lead molecules and provide a rationale for further molecular studies to explain their usefulness as potential inhibitors of the hypoxia-inducible factor 1 (HIF1). Full article

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Open AccessArticle

Eurycomanone and Eurycomanol from Eurycoma longifolia Jack as Regulators of Signaling Pathways Involved in Proliferation, Cell Death and Inflammation

by Shéhérazade Hajjouli, Sébastien Chateauvieux, Marie-Hélène Teiten, Barbora Orlikova, Marc Schumacher, Mario Dicato, Chee-Yan Choo and Marc Diederich

Molecules 2014, 19(9), 14649-14666; https://doi.org/10.3390/molecules190914649 - 16 Sep 2014

Cited by 42 | Viewed by 13642

Abstract

Eurycomanone and eurycomanol are two quassinoids from the roots of Eurycoma longifolia Jack. The aim of this study was to assess the bioactivity of these compounds in Jurkat and K562 human leukemia cell models compared to peripheral blood mononuclear cells from healthy donors. [...] Read more.

Eurycomanone and eurycomanol are two quassinoids from the roots of Eurycoma longifolia Jack. The aim of this study was to assess the bioactivity of these compounds in Jurkat and K562 human leukemia cell models compared to peripheral blood mononuclear cells from healthy donors. Both eurycomanone and eurycomanol inhibited Jurkat and K562 cell viability and proliferation without affecting healthy cells. Interestingly, eurycomanone inhibited NF-κB signaling through inhibition of IκBα phosphorylation and upstream mitogen activated protein kinase (MAPK) signaling, but not eurycomanol. In conclusion, both quassinoids present differential toxicity towards leukemia cells, and the presence of the α,β-unsaturated ketone in eurycomanone could be prerequisite for the NF-κB inhibition. Full article

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Design and Synthesis of New Cholesterol-Conjugated 5-Fluorouracil: A Novel Potential Delivery System for Cancer Treatment

by Awwad A. Radwan and Fares K. Alanazi

Molecules 2014, 19(9), 13177-13187; https://doi.org/10.3390/molecules190913177 - 26 Aug 2014

Cited by 45 | Viewed by 8879

Abstract

Cholesterol-conjugated 5-fluorouracil prodrugs were designed to be carried in vivo via low density lipoproteins (LDL) and subsequently undergo LDL-receptor-mediated internalisation into cancer cells. In vivo anti-cancer evaluation was performed using 5-fluorouracil-cholesterol conjugate in a mouse model. The obtained prodrugs were more potent than [...] Read more.

Cholesterol-conjugated 5-fluorouracil prodrugs were designed to be carried in vivo via low density lipoproteins (LDL) and subsequently undergo LDL-receptor-mediated internalisation into cancer cells. In vivo anti-cancer evaluation was performed using 5-fluorouracil-cholesterol conjugate in a mouse model. The obtained prodrugs were more potent than 5-fluorouracil control drug at the same 5-fluorouracil content (3 mg·kg⁻¹). Full article

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Open AccessArticle

Isocorydine Derivatives and Their Anticancer Activities

by Mei Zhong, Yanjuan Liu, Junxi Liu, Duolong Di, Mengrou Xu, Yaya Yang, Wenguang Li, Yali Chen and Jinxia Liu

Molecules 2014, 19(8), 12099-12115; https://doi.org/10.3390/molecules190812099 - 12 Aug 2014

Cited by 27 | Viewed by 8364

Abstract

In order to improve the anticancer activity of isocorydine (ICD), ten isocorydine derivatives were prepared through chemical structure modifications, and their in vitro and in vivo activities were experimentally investigated. 8-Amino-isocorydine (8) and 6a,7-dihydrogen-isocorydione (10) could inhibit the growth [...] Read more.

In order to improve the anticancer activity of isocorydine (ICD), ten isocorydine derivatives were prepared through chemical structure modifications, and their in vitro and in vivo activities were experimentally investigated. 8-Amino-isocorydine (8) and 6a,7-dihydrogen-isocorydione (10) could inhibit the growth of human lung (A549), gastric (SGC7901) and liver (HepG2) cancer cell lines in vitro. Isocorydione (2) could inhibit the tumor growth of murine sarcoma S₁₈₀-bearing mice, and 8-acetamino-isocorydine (11), a pro-drug of 8-amino-isocorydine (8), which is instable in water solution at room temperature, had a good inhibitory effect on murine hepatoma H₂₂-induced tumors. The results suggested that the isocorydine structural modifications at C-8 could significantly improve the biological activity of this alkaloid, indicating its suitability as a lead compound in the development of an effective anticancer agent. Full article

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Aqueous Solubility and Degradation Kinetics of the Phytochemical Anticancer Thymoquinone; Probing the Effects of Solvents, pH and Light

by Jumah Masoud M. Salmani, Sajid Asghar, Huixia Lv and Jianping Zhou

Molecules 2014, 19(5), 5925-5939; https://doi.org/10.3390/molecules19055925 - 8 May 2014

Cited by 127 | Viewed by 12429

Abstract

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite [...] Read more.

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite their direct correlation with the in vivo efficacy. In the current research, we have established and validated a stability-indicating HPLC method for the detection of TQ and its degradation products under different conditions. We then investigated the solubility and stability profiles of TQ in aqueous solutions. The stability study was aimed to determine the effect of pH, solvent type and light on the degradation process of TQ, along with the investigation of the kinetics of this degradation. The solubility of TQ varied in different aqueous solvents, and might be compromised due to stability issues. However, these findings confirm that the aqueous solubility is not the major obstacle for the drug formulations mainly due to the considerable water solubility (>500 μg/mL) that may be enough to exert pharmacologic effects if administered via parenteral route. Stability study results showed a very low stability profile of TQ in all the aqueous solutions with rapid degradation that varied with solvent type. The study of the degradation kinetics showed a significant effect of pH on the degradation process. The process followed first order kinetics at more acidic and alkaline pH values, and second order kinetics at pH 5–7.4, regardless of the solvent type. The results also expressed that light has a greater impact on the stability of TQ as a shorter period of exposure led to severe degradation, independent of the solution pH and solvent type. Our results also addressed some discrepancies in previously published researches regarding the formulation and quantification of TQ with suggested solutions. Overall, the current study concludes that TQ is unstable in aqueous solutions, particularly at an alkaline pH, in addition to presenting severe light sensitivity. This data indicates the inappropriateness of aqueous solutions as pharmaceutical vehicles for TQ preparations. To the best of our knowledge, this is the first study describing TQ aqueous solubility and stability that may lead to the development of a stable and effective TQ formulation. Full article

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Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments

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