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Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities
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Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 9952

Special Issue Editor

Prof. Dr. Saiyang Zhang

E-Mail Website
Guest Editor
School of Basic Medical Science, Zhengzhou University, Zhengzhou 450001, China
Interests: tubulin; Hippo pathway; NEDDylation; FAK; HDAC

Special Issue Information

Dear Colleagues,

Small-molecule chemical drugs are the most important tools in the treatment of many diseases, including cancer. The discovery of novel small-molecule inhibitors for different targets holds the promise of improving the effectiveness of existing treatments and avoiding or mitigating adverse effects. In tumor research, an increasing number of critical proteins and signaling pathways related to tumorigenesis are being discovered, providing a variety of research ideas for medicinal chemistry studies.

This Special Issue on “Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities” will focus on the discovery, design and synthesis of novel small-molecule inhibitors in chemotherapy, the validation of their biological activity, and the exploration of their mechanism of effect. It will provide a platform for communication and data support for the discovery of novel small-molecule inhibitors.

Prof. Dr. Saiyang Zhang
Guest Editor

Manuscript Submission Information

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Published Papers (5 papers)

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Research

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13 pages, 455 KiB  
Article
Chemical Constituents and Anticancer Activities of Marine-Derived Fungus Trichoderma lixii
by Natchanun Sirimangkalakitti, Jianyu Lin, Kazuo Harada, Andi Setiawan, Mitsuhiro Arisawa and Masayoshi Arai
Molecules 2024, 29(9), 2048; https://doi.org/10.3390/molecules29092048 - 29 Apr 2024
Viewed by 1439
Abstract
The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation [...] Read more.
The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A (1), trichodermamide B (2), aspergillazine A (3), DC1149B (4), ergosterol peroxide (5), cerebrosides D/C (6/7), 5-hydroxy-2,3-dimethyl-7-methoxychromone (8), nafuredin A (9), and harzianumols E/F (10/11). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5–11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2, 4, and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC50 of 22.43 μM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)
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17 pages, 2912 KiB  
Article
Synthesis and Antiproliferative Activity of 2,6-Disubstituted Imidazo[4,5-b]pyridines Prepared by Suzuki Cross Coupling
by Ida Boček Pavlinac, Mirna Dragić, Leentje Persoons, Dirk Daelemans and Marijana Hranjec
Molecules 2023, 28(20), 7208; https://doi.org/10.3390/molecules28207208 - 21 Oct 2023
Viewed by 1468
Abstract
A series of novel 2,6-diphenyl substituted imidazo[4,5-b]pyridines was designed and synthesized using optimized Suzuki cross coupling to evaluate their biological activity in vitro. The conditions of the Suzuki coupling were evaluated and optimized using a model reaction. To study the [...] Read more.
A series of novel 2,6-diphenyl substituted imidazo[4,5-b]pyridines was designed and synthesized using optimized Suzuki cross coupling to evaluate their biological activity in vitro. The conditions of the Suzuki coupling were evaluated and optimized using a model reaction. To study the influence of the substituents on the biological activity, we prepared N-unsubstituted and N-methyl substituted imidazo[4,5-b]pyridines with different substituents at the para position on the phenyl ring placed at position 6 on the heterocyclic scaffold. Antiproliferative activity was determined on diverse human cancer cell lines, and the selectivity of compounds with promising antiproliferative activity was determined on normal peripheral blood mononuclear cells (PBMC). Pronounced antiproliferative activity was observed for p-hydroxy substituted derivatives 13 and 19, both displaying strong activity against most of the tested cell lines (IC50 1.45–4.25 μM). The unsubstituted N-methyl derivative 19 proved to be the most active derivative. There was a dose-dependent accumulation of G2/M arrested cells in several cancer cell lines after exposure to compound 19, implying a cell cycle-phase-specific mechanism of action. Additionally, the novel series of derivatives was evaluated for antiviral activity against a broad panel of viruses, yet the majority of tested compounds did not show antiviral activity. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)
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19 pages, 5471 KiB  
Article
Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin’s Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles
by Abdalrahim M. Ali, Alaa A. Makki, Walaa Ibraheem, Mohammed Abdelrahman, Wadah Osman, Asmaa E. Sherif, Ahmed Ashour, Sabrin R. M. Ibrahim, Kholoud F. Ghazawi, Waad A. Samman and Abdulrahim A. Alzain
Molecules 2023, 28(5), 2289; https://doi.org/10.3390/molecules28052289 - 1 Mar 2023
Cited by 3 | Viewed by 2869
Abstract
Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve [...] Read more.
Non-Hodgkin’s lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin’s lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin’s lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between −7.66 and −8.42 Kcal/mol. The docking analysis of ligand–receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with −52.22 Kcal/mol. To identify the structural changes and the complexes’ stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand–protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with −29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)
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17 pages, 4492 KiB  
Article
Anticancer Activity of (±)-Kusunokinin Derivatives towards Cholangiocarcinoma Cells
by Thidarath Rattanaburee, Patpanat Sermmai, Kornthip Tangthana-umrung, Tienthong Thongpanchang and Potchanapond Graidist
Molecules 2022, 27(23), 8291; https://doi.org/10.3390/molecules27238291 - 28 Nov 2022
Cited by 4 | Viewed by 1840
Abstract
This study aimed to investigate the cytotoxicity and anticancer activity of (±)-kusunokinin derivatives ((±)-TTPG-A and (±)-TTPG-B). The cytotoxicity effect was performed on human cancer cells, including breast cancer, cholangiocarcinoma, colon and ovarian cancer-cells, compared with normal cells, using the MTT assay. Cell-cycle arrest [...] Read more.
This study aimed to investigate the cytotoxicity and anticancer activity of (±)-kusunokinin derivatives ((±)-TTPG-A and (±)-TTPG-B). The cytotoxicity effect was performed on human cancer cells, including breast cancer, cholangiocarcinoma, colon and ovarian cancer-cells, compared with normal cells, using the MTT assay. Cell-cycle arrest and apoptosis were detected using flow-cytometry analysis. We found that (±)-TTPG-B exhibited the strongest cytotoxicity on aggressive breast-cancer (MDA-MB-468 and MDA-MB-231) and cholangiocarcinoma (KKU-M213), with an IC50 value of 0.43 ± 0.01, 1.83 ± 0.04 and 0.01 ± 0.001 µM, respectively. Interestingly, (±)-TTPG-A and (±)-TTPG-B exhibited less toxicity than (±)-kusunokinin (9.75 ± 0.39 µM) on L-929 cells (normal fibroblasts). Moreover, (±)-TTPG-A predominated the ell-cycle arrest at the S phase, while (±)-TTPG-B caused cell arrest at the G0/G1 phase, in the same way as (±)-kusunokinin in KKU-M213 cells. Both (±)-TTPG-A and (±)-TTPG-B induced apoptosis and multi-caspase activity more than (±)-kusunokinin. Taken together, we conclude that (±)-TTPG-A and (±)-TTPG-B have a strong anticancer effect on cholangiocarcinoma. Moreover, (±)-TTPG-B could be a potential candidate compound for breast cancer and cholangiocarcinoma in the future. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)
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17 pages, 3974 KiB  
Review
The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus
by Zhaowen Pan, Lan Huang, Yuanyuan Gan, Yan Xia and Wei Yu
Molecules 2024, 29(12), 2852; https://doi.org/10.3390/molecules29122852 - 15 Jun 2024
Cited by 2 | Viewed by 1408
Abstract
In the field of human health research, the homeostasis of copper (Cu) is receiving increased attention due to its connection to pathological conditions, including diabetes mellitus (DM). Recent studies have demonstrated that proteins associated with Cu homeostasis, such as ATOX1, FDX1, ATP7A, ATPB, [...] Read more.
In the field of human health research, the homeostasis of copper (Cu) is receiving increased attention due to its connection to pathological conditions, including diabetes mellitus (DM). Recent studies have demonstrated that proteins associated with Cu homeostasis, such as ATOX1, FDX1, ATP7A, ATPB, SLC31A1, p53, and UPS, also contribute to DM. Cuproptosis, characterized by Cu homeostasis dysregulation and Cu overload, has been found to cause the oligomerization of lipoylated proteins in mitochondria, loss of iron–sulfur protein, depletion of glutathione, production of reactive oxygen species, and cell death. Further research into how cuproptosis affects DM is essential to uncover its mechanism of action and identify effective interventions. In this article, we review the molecular mechanism of Cu homeostasis and the role of cuproptosis in the pathogenesis of DM. The study of small-molecule drugs that affect these proteins offers the possibility of moving from symptomatic treatment to treating the underlying causes of DM. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)
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