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Discovery of Small Molecules for Cancer Therapy: Current Challenges, Recent Trends, and Future Perspectives

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

Deadline for manuscript submissions: 30 June 2024 | Viewed by 4335

Special Issue Editors

Prof. Dr. Mehlika Dilek Altıntop

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Turkey
Interests: anticancer drug discovery; cancer-related kinases; drugs acting on cell death networks; small molecules; rational drug design; medicinal chemistry; heterocyclic chemistry; computational chemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ahmet Özdemir

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Turkey
Interests: targeted anticancer drug discovery; small molecules; rational drug design; medicinal chemistry; heterocyclic chemistry

Special Issue Information

Dear Colleagues,

Cancer is a group of diseases in which the rapid, uncontrolled, and pathological proliferation of abnormal cells occurs. Despite substantial breakthroughs in the diagnosis, prevention, and treatment of the disease, cancer continues to pose a formidable threat to global public health, causing the death of millions of people around the world.

In the search for more efficient therapies devoid of the drawbacks of traditional cytotoxic chemotherapy, targeted therapies have appeared as a promising approach to maximize therapeutic benefits with negligible side effects. Continuous and significant advances in the understanding of the multi-factorial pathogenesis of cancer have empowered a constant discovery of potential molecular targets and the development of novel targeted therapeutics. Small molecules have advantages over macromolecules for the targeted therapy of cancer in terms of pharmacokinetic profiles, costs, patient compliance, and so on.

This Special Issue aims to examine current challenges and recent trends and provide future perspectives to pave the way for small molecule anticancer drug discovery. We would like to invite you to submit research articles and reviews relevant to the discovery of small molecules for cancer therapy.

We look forward to receiving your contributions.

Prof. Dr. Mehlika Dilek Altıntop
Prof. Dr. Ahmet Özdemir
Guest Editors

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
  • targeted therapy
  • anticancer drug discovery
  • lead identification
  • small molecules
  • cancer-related targets
  • signaling pathways related to cancer
  • emerging approaches to anticancer drug design

Published Papers (3 papers)

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Research

15 pages, 9991 KiB  
Article
Effect of Fragment 1 on the Binding of Epigallocatechin Gallate to the PD-L1 Dimer Explored by Molecular Dynamics
by Yan Guo, Yilin Guo, Zichao Guo, Boping Liu and Jianguo Xu
Molecules 2023, 28(23), 7881; https://doi.org/10.3390/molecules28237881 - 30 Nov 2023
Cited by 1 | Viewed by 646
Abstract
Blocking the interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) by directly targeting the PD-L1 dimer has emerged as a hot topic in the field of cancer immunotherapy. Epigallocatechin gallate (EGCG), a natural product, has been demonstrated binding to [...] Read more.
Blocking the interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) by directly targeting the PD-L1 dimer has emerged as a hot topic in the field of cancer immunotherapy. Epigallocatechin gallate (EGCG), a natural product, has been demonstrated binding to the PD-L1 dimer in our previous study, but has a weaker binding capacity, moreover, EGCG is located at the end of the binding pocket of the PD-L1 dimer. The inhibitor fragment 1 (FRA) lies at the other end. So, we proposed that the introduction of FRA might be able to improve the binding ability. To illuminate this issue, molecular dynamics (MD) simulation was performed in the present study. Binding free energy calculations show that the binding affinity is significantly increased by 17 kcal/mol upon the introduction of FRA. It may be due to the energy contributions of emerging key residues ATyr56, AMet115, BTyr123, AIle54 and the enhanced contributions of initial key residues ATyr123 and BVal68. Binding mode and non-bonded interaction results indicate that FRA_EGCG (EGCG in combination with FRA) binds to the C-, F- and G-sheet of the PD-L1 dimer. Importantly, the introduction of FRA mainly strengthened the nonpolar interactions. The free energy landscape and secondary structure results further show that FRA_EGCG can interact with the PD-L1 dimer more stably. These data demonstrated here provide the theoretical basis for screening two or more natural products with additive inhibitory effect on this pathway and therefore exerting more effective anticancer immunity. Full article
(This article belongs to the Special Issue Discovery of Small Molecules for Cancer Therapy: Current Challenges, Recent Trends, and Future Perspectives)
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12 pages, 4544 KiB  
Article
Design, Synthesis, and Acute Toxicity Assays for Novel Thymoquinone Derivative TQFL12 in Mice and the Mechanism of Resistance to Toxicity
by Ting Li, Qi Tan, Chunli Wei, Hui Zou, Xiaoyan Liu, Zhiqiang Mei, Pengfei Zhang, Jingliang Cheng and Junjiang Fu
Molecules 2023, 28(13), 5149; https://doi.org/10.3390/molecules28135149 - 30 Jun 2023
Viewed by 1046
Abstract
TQFL12 is a novel derivative designed and synthesized on the basis of Thymoquinone (TQ) which is extracted from Nigella sativa seeds. We have demonstrated that TQFL12 was more effective in the treatment of TNBC than TQ. In order to directly reflect the acute [...] Read more.
TQFL12 is a novel derivative designed and synthesized on the basis of Thymoquinone (TQ) which is extracted from Nigella sativa seeds. We have demonstrated that TQFL12 was more effective in the treatment of TNBC than TQ. In order to directly reflect the acute toxicity of TQFL12 in vivo, in this study, we designed, synthesized, and compared it with TQ. The mice were administered drugs with different concentration gradients intraperitoneally, and death was observed within one week. The 24 h median lethal dose (LD50) of TQ was calculated to be 33.758 mg/kg, while that of TQFL12 on the 7th day was 81.405 mg/kg, and the toxicity was significantly lower than that of TQ. The liver and kidney tissues of the dead mice were observed by H&E staining. The kidneys of the TQ group had more severe renal damage, while the degree of the changes in the TQFL12 group was obviously less than that in the TQ group. Western blotting results showed that the expressions of phosphorylated levels of adenylate-activated protein kinase AMPKα were significantly up-regulated in the kidneys of the TQFL12 group. Therefore, it can be concluded that the acute toxicity of TQFL12 in vivo is significantly lower than that of TQ, and its anti-toxicity mechanism may be carried out through the AMPK signaling pathway, which has a good prospect for drug development. Full article
(This article belongs to the Special Issue Discovery of Small Molecules for Cancer Therapy: Current Challenges, Recent Trends, and Future Perspectives)
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23 pages, 3974 KiB  
Article
Design, Synthesis, and Antiproliferative Activity of Benzopyran-4-One-Isoxazole Hybrid Compounds
by Shilpi Gupta, Shang Eun Park, Saghar Mozaffari, Bishoy El-Aarag, Keykavous Parang and Rakesh Kumar Tiwari
Molecules 2023, 28(10), 4220; https://doi.org/10.3390/molecules28104220 - 21 May 2023
Cited by 1 | Viewed by 2035
Abstract
The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell [...] Read more.
The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a–d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC50 values were in the range of 5.2–22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC50 values of 5a–d against normal HEK-293 cells were in the range of 102.4–293.2 μM. Compound 5a was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly 5a–d, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound 5a exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis. Full article
(This article belongs to the Special Issue Discovery of Small Molecules for Cancer Therapy: Current Challenges, Recent Trends, and Future Perspectives)
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