Submit to Molecules Review for Molecules Propose a Special Issue

Journal Browser

► Journal Browser

Anticancer Agents: Design, Synthesis and Evaluation III

Special Issue Editors
Special Issue Information
Keywords
Related Special Issues
Published Papers

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 March 2023) | Viewed by 18371

Share This Special Issue

Special Issue Editor

Prof. Dr. Qiao-Hong Chen

E-Mail Website
Guest Editor

Department of Chemistry and Biochemistry, California State University, Fresno 2555 E. San Ramon Ave. M/S SB70, Fresno, CA 93740, USA
Interests: anticancer agents; medicinal chemistry; natural products; bioorganic chemistry; organic synthesis; drug design and synthesis; prostate cancer; lead compound optimization; biological evaluation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cancer-related mortality rate still remains high due to the various limitations of the currently available therapies. The development of novel anticancer agents thus continues to be imperative to combat various deadly cancers. The emerging molecular targets, signal pathways, and drug-discovery technologies enable the development of novel strategies for the rational design of new anticancer agents. Numerous well-established synthetic methods and biological screening assays have paved the way for the discovery and development of new anticancer agents. The third edition of this Special Issue of Molecules continues to be devoted to all aspects of recent exploitation for new anticancer agents. We welcome the submission of both original research and review articles, focusing on rational design, synthesis, and/or biological evaluation of various agents (including small molecules, natural products, endogenous molecules, antibodies, and vaccines) as potential cancer therapeutics, for publication in this Special Issue.

Prof. Dr. Qiao-Hong Chen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer drug discovery
cancer drug development
medicinal synthesis
cancer therapy
chemotherapeutics
anticancer activity
rational drug design
Structure-activity relationship
cancer therapeutics
anticancer agent
antitumor agent
biological evaluation
cancer bioassay
cancer screening assay
natural product
small molecule enzyme inhibitor
receptor antagonist
lead optimization
structure modification
structure manipulation
anti-proliferative activity
cytotoxicity
cell apoptosis
cancer cell models
anti-tumor efficacy

Related Special Issues

Anticancer Agents: Design, Synthesis and Evaluation in Molecules (32 articles)
Anticancer Agents: Design, Synthesis and Evaluation II in Molecules (11 articles)

Published Papers (10 papers)

Download All Papers

Research

23 pages, 6225 KiB

Open AccessArticle

A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins

by Snehal Nirgude, Shahana M. V., Febina Ravindran, Sujeet Kumar, Shivangi Sharma, Raghunandan Mahadeva, Anisha Mhatre, Subhas S. Karki and Bibha Choudhary

Molecules 2023, 28(13), 5226; https://doi.org/10.3390/molecules28135226 - 5 Jul 2023

Viewed by 1354

Abstract

Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease’s aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

15 pages, 1349 KiB

Open AccessArticle

Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells

by Inderpal Sekhon, Guanglin Chen, Keyara Piri, Seiji Shinkawa, Dennis Ashong, Qiang Zhang, Guangdi Wang and Qiao-Hong Chen

Molecules 2023, 28(12), 4743; https://doi.org/10.3390/molecules28124743 - 13 Jun 2023

Viewed by 1457

Abstract

Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential N-terminal AR antagonist, this study aims to explore the structure–activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation. Dehydroabietylamine, abietic acid, dehydroabietic acid, and their derivatives were selected, since they have a similar core structure as QW07. Twenty diterpenoids were prepared for the evaluation of their antiproliferative potency on AR-positive prostate cancer cell models (LNCaP and 22Rv1) using AR-null cell models (PC-3 and DU145) as comparisons. Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC₅₀ = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

23 pages, 3594 KiB

Open AccessArticle

Discovery of New 2-Phenylamino-3-acyl-1,4-naphthoquinones as Inhibitors of Cancer Cells Proliferation: Searching for Intra-Cellular Targets Playing a Role in Cancer Cells Survival

by Julio Benites, Jaime A. Valderrama, Álvaro Contreras, Cinthya Enríquez, Ricardo Pino-Rios, Osvaldo Yáñez and Pedro Buc Calderon

Molecules 2023, 28(11), 4323; https://doi.org/10.3390/molecules28114323 - 24 May 2023

Cited by 2 | Viewed by 1931

Abstract

A series of 2-phenylamino-3-acyl-1,4-naphtoquinones were evaluated regarding their in vitro antiproliferative activities using DU-145, MCF-7 and T24 cancer cells. Such activities were discussed in terms of molecular descriptors such as half-wave potentials, hydrophobicity and molar refractivity. Compounds 4 and 11 displayed the highest antiproliferative activity against the three cancer cells and were therefore further investigated. The in silico prediction of drug likeness, using pkCSM and SwissADME explorer online, shows that compound 11 is a suitable lead molecule to be developed. Moreover, the expressions of key genes were studied in DU-145 cancer cells. They include genes involved in apoptosis (Bcl-2), tumor metabolism regulation (mTOR), redox homeostasis (GSR), cell cycle regulation (CDC25A), cell cycle progression (TP53), epigenetic (HDAC4), cell-cell communication (CCN2) and inflammatory pathways (TNF). Compound 11 displays an interesting profile because among these genes, mTOR was significantly less expressed as compared to control conditions. Molecular docking shows that compound 11 has good affinity with mTOR, unraveling a potential inhibitory effect on this protein. Due to the key role of mTOR on tumor metabolism, we suggest that impaired DU-145 cells proliferation by compound 11 is caused by a reduced mTOR expression (less mTOR protein) and inhibitory activity on mTOR protein. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Figure 1

24 pages, 3883 KiB

Open AccessArticle

Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

by Razan Eskandrani, Lamees S. Al-Rasheed, Siddique Akber Ansari, Ahmed H. Bakheit, Abdulrahman A. Almehizia, Maha Almutairi and Hamad M. Alkahtani

Molecules 2023, 28(11), 4271; https://doi.org/10.3390/molecules28114271 - 23 May 2023

Cited by 4 | Viewed by 1571

Abstract

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC₅₀ = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC₅₀ = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC₅₀ = 0.059 µM). All the compounds satisfied the Lipinski’s rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol–water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Figure 1

31 pages, 7189 KiB

Open AccessArticle

Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 Activators

by Huiqing Chen, Zekun Liu, Lixin Gao, Li-Fang Yu, Yubo Zhou, Jie Tang, Jia Li and Fan Yang

Molecules 2023, 28(6), 2488; https://doi.org/10.3390/molecules28062488 - 8 Mar 2023

Viewed by 1651

Abstract

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor member of the protein tyrosine phosphatase (PTP) family, negatively regulates several signaling pathways that are responsible for pathological cell processes in cancers. In this study, we report a series of 3-amino-4,4-dimethyl lithocholic acid derivatives as SHP1 activators. The most potent compounds, 5az-ba, showed low micromolar activating effects (EC₅₀: 1.54–2.10 μM) for SHP1, with 7.63–8.79-fold maximum activation and significant selectivity over the closest homologue Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) (>32-fold). 5az-ba showed potent anti-tumor effects with IC₅₀ values of 1.65–5.51 μM against leukemia and lung cancer cells. A new allosteric mechanism of SHP1 activation, whereby small molecules bind to a central allosteric pocket and stabilize the active conformation of SHP1, was proposed. The activation mechanism was consistent with the structure–activity relationship (SAR) data. This study demonstrates that 3-amino-4,4-dimethyl lithocholic acid derivatives can be selective SHP1 activators with potent cellular efficacy. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

16 pages, 2922 KiB

Open AccessArticle

Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors

by Hamad M. Alkahtani, Amer Alhaj Zen, Ahmad J. Obaidullah, Mohammed M. Alanazi, Abdulrahman A. Almehizia, Siddique Akber Ansari, Fadilah Sfouq Aleanizy, Fulwah Yahya Alqahtani, Rana M. Aldossari, Raghad Abdullah Algamdi, Lamees S. Al-Rasheed, Sami G. Abdel-Hamided, Alaa A.-M. Abdel-Aziz and Adel S. El-Azab

Molecules 2023, 28(1), 120; https://doi.org/10.3390/molecules28010120 - 23 Dec 2022

Cited by 3 | Viewed by 2154

Abstract

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC₅₀ values of 0.115, 0.131, and 0.142 μM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski’s rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Figure 1

20 pages, 7265 KiB

Open AccessArticle

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

by Chanchal Kiran Thakur, Rabin Neupane, Chandrabose Karthikeyan, Charles R. Ashby, Jr., R. Jayachandra Babu, Sai H. S. Boddu, Amit K. Tiwari and Narayana Subbiah Hari Narayana Moorthy

Molecules 2022, 27(21), 7461; https://doi.org/10.3390/molecules27217461 - 2 Nov 2022

Cited by 11 | Viewed by 2023

Abstract

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug–loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin–loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

14 pages, 1194 KiB

Open AccessArticle

Synthesis of Novel Lipophilic Polyamines via Ugi Reaction and Evaluation of Their Anticancer Activity

by Artemiy Nichugovskiy, Varvara Maksimova, Ekaterina Trapeznikova, Elizaveta Eshtukova-Shcheglova, Igor Ivanov, Marianna Yakubovskaya, Kirill Kirsanov, Dmitry Cheshkov, Gian Cesare Tron and Mikhail Maslov

Molecules 2022, 27(19), 6218; https://doi.org/10.3390/molecules27196218 - 21 Sep 2022

Cited by 3 | Viewed by 2099

Abstract

Natural polyamines (PAs) are involved in the processes of proliferation and differentiation of cancer cells. Lipophilic synthetic polyamines (LPAs) induce the cell death of various cancer cell lines. In the current paper, we have demonstrated a new method for synthesis of LPAs via the multicomponent Ugi reaction and subsequent reduction of amide groups by PhSiH₃. The anticancer activity of the obtained compounds was evaluated in the A-549, MCF7, and HCT116 cancer cell lines. For the first time, it was shown that the anticancer activity of LPAs with piperazine fragments is comparable with that of aliphatic LPAs. The presence of a diglyceride fragment in the structure of LPAs appears to be a key factor for the manifestation of high anticancer activity. The findings of the study strongly support further research in the field of LPAs and their derivatives. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

20 pages, 6132 KiB

Open AccessArticle

Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers

by Han Yao, Yuanyuan Ren, Jun Yan, Jiadai Liu, Jinhui Hu, Ming Yan and Xingshu Li

Molecules 2022, 27(17), 5359; https://doi.org/10.3390/molecules27175359 - 23 Aug 2022

Viewed by 1735

Abstract

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC₅₀ value of 0.002 μM, compared to tepotinib (IC₅₀ = 0.013 μM). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G₁ phase in a dose-dependent fashion. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures

Graphical abstract

16 pages, 2135 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Synthetic Indolone Derivatives as Anti-Tumor Agents Targeting p53-MDM2 and p53-MDMX

by Yali Wang, Bo Ji, Zhongshui Cheng, Lianghui Zhang, Yingying Cheng, Yingying Li, Jin Ren, Wenbo Liu and Yuanyuan Ma

Molecules 2022, 27(12), 3721; https://doi.org/10.3390/molecules27123721 - 9 Jun 2022

Cited by 4 | Viewed by 1614

Abstract

A series of novel indolone derivatives were synthesized and evaluated for their binding affinities toward MDM2 and MDMX. Some compounds showed potent MDM2 and moderate MDMX activities. Among them, compound A13 exhibited the most potent affinity toward MDM2 and MDMX, with a K_i of 0.031 and 7.24 μM, respectively. A13 was also the most potent agent against HCT116, MCF7, and A549, with IC₅₀ values of 6.17, 11.21, and 12.49 μM, respectively. Western blot analysis confirmed that A13 upregulated the expression of MDM2, MDMX, and p53 by Western blot analysis. These results indicate that A13 is a potent dual p53-MDM2 and p53-MDMX inhibitor and deserves further investigation. Full article

(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation III)

► Show Figures