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Nature-Inspired Antitumor Agents
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Nature-Inspired Antitumor Agents

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 38942

Special Issue Editors

Dr. Maria Emília De Sousa

E-Mail Website1 Website2
Guest Editor
1. Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), 4450-208 Porto, Portugal
2. Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: medicinal chemistry; organic synthesis; heterocycles; P-glycoprotein; anticancer; antimicrobials; chiral drugs; marine natural products
Special Issues, Collections and Topics in MDPI journals
Dr. Honorina Cidade

E-Mail Website
Guest Editor
Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal
Interests: medicinal chemistry; organic synthesis; drug discovery; anticancer activity; antimicrobial activity; chiral drugs; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Medicinal chemistry in the twenty-first century has undergone innovative changes due to revolutions in biotechnology and informatics. These advances are mainly in the lead optimization process, but a very significant portion of these leads will continue to have molecules originated from natural products (NPs). The diversity of species from terrestrial plants, animals, microorganisms, and marine organisms results in a multitude of secondary metabolites with novel chemical structures and innovative mechanisms of action.

This renaissance of NPs is most allied with the total synthesis, semi-synthesis, and analogue-based design. Nevertheless, other biotechnology and cheminformatics approaches are being used to emerge leads from nature. Among the activities of NPs, antitumor activity stands out. NPs like doxorubicin and taxol have their place in chemotherapy alongside new immunotherapies.

This Special Issue focuses on the breakthroughs that are being made to develop new antitumor agents inspired by the variety of NPs that are emerging as chemotherapeutics, and intends to collect the state-of-the-art with original research and review articles that consider NP analogues as potential antitumor drug candidates. You are welcome to generate a unique topic.

Prof. Dr. Maria Emília de Sousa
Dr. Honorina Cidade
Guest Editors

Manuscript Submission Information

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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

  • natural products
  • antitumor activity
  • NPs analogues-based design

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Related Special Issue

Published Papers (9 papers)

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Research

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11 pages, 1383 KiB  
Communication
Effect of 1-Carbaldehyde-3,4-dimethoxyxanthone on Prostate and HPV-18 Positive Cervical Cancer Cell Lines and on Human THP-1 Macrophages
by Rui Medeiros, Bruno Horta, Joana Freitas-Silva, Jani Silva, Francisca Dias, Emília Sousa, Madalena Pinto and Fátima Cerqueira
Molecules 2021, 26(12), 3721; https://doi.org/10.3390/molecules26123721 - 18 Jun 2021
Cited by 2 | Viewed by 2933
Abstract
Xanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), [...] Read more.
Xanthone derivatives have shown promising antitumor properties, and 1-carbaldehyde-3,4-dimethoxyxanthone (1) has recently emerged as a potent tumor cell growth inhibitor. In this study, its effect was evaluated (MTT viability assay) against a new panel of cancer cells, namely cervical cancer (HeLa), androgen-sensitive (LNCaP) and androgen-independent (PC-3) prostate cancer, and nonsolid tumor derived cancer (Jurkat) cell lines. The effect of xanthone 1 on macrophage functions was also evaluated. The effect of xanthone 1-conditioned THP-1 human macrophage supernatants on the metabolic viability of cervical and prostate cancer cell lines was determined along with its interference with cytokine expression characteristic of M1 profile (IL-1 ≤ β; TNF-α) or M2 profile (IL-10; TGF-β) (PCR and ELISA). Nitric oxide (NO) production by murine RAW264.7 macrophages was quantified by Griess reaction. Xanthone 1 (20 μM) strongly inhibited the metabolic activity of the cell lines and was significantly more active against prostate cell lines compared to HeLa (p < 0.05). Jurkat was the cell most sensitive to the effect of xanthone 1. Compound 1-conditioned IL-4-stimulated THP-1 macrophage supernatants significantly (p < 0.05) inhibited the metabolic activity of HeLa, LNCaP, and PC-3. Xanthone 1 did not significantly affect the expression of cytokines by THP-1 macrophages. The inhibiting effect of compound 1 observed on the production of NO by RAW 264.7 macrophages was moderate. In conclusion, 1-carbaldehyde-3,4-dimethoxyxanthone (1) decreases the metabolic activity of cancer cells and seems to be able to modulate macrophage functions. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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17 pages, 2978 KiB  
Article
A New Chalcone Derivative with Promising Antiproliferative and Anti-Invasion Activities in Glioblastoma Cells
by Daniel Mendanha, Joana Vieira de Castro, Joana Moreira, Bruno M. Costa, Honorina Cidade, Madalena Pinto, Helena Ferreira and Nuno M. Neves
Molecules 2021, 26(11), 3383; https://doi.org/10.3390/molecules26113383 - 3 Jun 2021
Cited by 13 | Viewed by 3826
Abstract
Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer [...] Read more.
Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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15 pages, 3073 KiB  
Article
Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53
by Solida Long, Joana B. Loureiro, Carla Carvalho, Luís Gales, Lucília Saraiva, Madalena M. M. Pinto, Ploenthip Puthongking and Emília Sousa
Molecules 2021, 26(6), 1637; https://doi.org/10.3390/molecules26061637 - 15 Mar 2021
Cited by 3 | Viewed by 2496
Abstract
The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as [...] Read more.
The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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17 pages, 3546 KiB  
Article
A Pyranoxanthone as a Potent Antimitotic and Sensitizer of Cancer Cells to Low Doses of Paclitaxel
by Fábio França, Patrícia M. A. Silva, José X. Soares, Ana C. Henriques, Daniela R. P. Loureiro, Carlos M. G. Azevedo, Carlos M. M. Afonso and Hassan Bousbaa
Molecules 2020, 25(24), 5845; https://doi.org/10.3390/molecules25245845 - 10 Dec 2020
Cited by 6 | Viewed by 2607
Abstract
Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors [...] Read more.
Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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10 pages, 1018 KiB  
Article
Norhierridin B, a New Hierridin B-Based Hydroquinone with Improved Antiproliferative Activity
by Pedro Brandão, Joana Moreira, Joana Almeida, Nair Nazareth, Ivo E. Sampaio-Dias, Vitor Vasconcelos, Rosário Martins, Pedro Leão, Madalena Pinto, Lucília Saraíva and Honorina Cidade
Molecules 2020, 25(7), 1578; https://doi.org/10.3390/molecules25071578 - 30 Mar 2020
Cited by 5 | Viewed by 4159
Abstract
Hierridin B (6), a methylated hydroquinone isolated from the marine picocyanobacterium Cyanobium sp. LEGE 06113, moderately inhibited the growth of colon adenocarcinoma HT-29 cells. Aiming to improve the potential antitumor activity of this natural product, the demethylated analogue, norhierridin B ( [...] Read more.
Hierridin B (6), a methylated hydroquinone isolated from the marine picocyanobacterium Cyanobium sp. LEGE 06113, moderately inhibited the growth of colon adenocarcinoma HT-29 cells. Aiming to improve the potential antitumor activity of this natural product, the demethylated analogue, norhierridin B (10), as well as its structurally-related quinone (9), were synthesized and evaluated for their growth inhibitory effect on a panel of human tumor cell lines, including the triple-negative breast cancer (TNBC) cells MDA-MB-231, SKBR3, and MDA-MB-468. Norhierridin B (10) showed a potent growth inhibitory effect on all cancer cell lines. Moreover, the growth inhibitory effect of compound 10 on MDA-MB-231 cells was associated with cell cycle arrest and apoptosis. Norhierridin B (10) interfered with several p53 transcriptional targets, increasing p21, Bax, and MDM2, while decreasing Bcl-2 protein levels, which suggested the potential activation of a p53 pathway. Altogether, these results evidenced a great improvement of the antitumor activity of hydroquinone 10 when compared to 6 and its structurally-related quinone (9). Notably, hydroquinone 10 displayed a prominent growth inhibitory activity against TNBC cells, which are characterized by high therapeutic resistance. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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14 pages, 2825 KiB  
Article
Evodiamine Mitigates Cellular Growth and Promotes Apoptosis by Targeting the c-Met Pathway in Prostate Cancer Cells
by Sun Tae Hwang, Jae-Young Um, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Acharan S. Narula, Ojas A. Namjoshi, Bruce E. Blough and Kwang Seok Ahn
Molecules 2020, 25(6), 1320; https://doi.org/10.3390/molecules25061320 - 13 Mar 2020
Cited by 28 | Viewed by 3885
Abstract
Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of [...] Read more.
Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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Review

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21 pages, 1538 KiB  
Review
Cannabinoids in Breast Cancer: Differential Susceptibility According to Subtype
by Cristina Ferreira Almeida, Natércia Teixeira, Georgina Correia-da-Silva and Cristina Amaral
Molecules 2022, 27(1), 156; https://doi.org/10.3390/molecules27010156 - 28 Dec 2021
Cited by 23 | Viewed by 9560
Abstract
Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding [...] Read more.
Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER−) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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24 pages, 1910 KiB  
Review
Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness
by Joana Moreira, Joana Almeida, Lucília Saraiva, Honorina Cidade and Madalena Pinto
Molecules 2021, 26(12), 3737; https://doi.org/10.3390/molecules26123737 - 19 Jun 2021
Cited by 23 | Viewed by 3153
Abstract
The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine [...] Read more.
The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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20 pages, 1096 KiB  
Review
Anticancer Potential of Raddeanin A, a Natural Triterpenoid Isolated from Anemone raddeana Regel
by Irum Naz, Shanaya Ramchandani, Muhammad Rashid Khan, Min Hee Yang and Kwang Seok Ahn
Molecules 2020, 25(5), 1035; https://doi.org/10.3390/molecules25051035 - 25 Feb 2020
Cited by 40 | Viewed by 4705
Abstract
Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an [...] Read more.
Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an anticancer agent, RA induces apoptosis, cell cycle arrest, inhibits invasion, migration and angiogenesis in malignant cell lines as well as in preclinical models. In this systemic review, the pharmacological effects of RA and its underlying molecular mechanisms were carefully analyzed and potential molecular targets have been highlighted. The apoptotic potential of RA can be mediated through the modulation of Bcl-2, Bax, caspase-3, caspase-8, caspase-9, cytochrome c and poly-ADP ribose polymerase (PARP) cleavage. PI3K/Akt signaling pathway serves as the major molecular target affected by RA. Furthermore, RA can block cell proliferation through inhibition of canonical Wnt/β-catenin signaling pathway in colorectal cancer cells. RA can also alter the activation of NF-κB and STAT3 signaling pathways to suppress invasion and metastasis. RA has also exhibited promising anticancer potential against drug resistant cancer cells and can enhance the anticancer effects of several chemotherapeutic agents. Overall, RA may function as a promising compound in combating cancer, although further in-depth study is required under clinical settings to validate its efficacy in cancer patients. Full article
(This article belongs to the Special Issue Nature-Inspired Antitumor Agents)
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