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Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities

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

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 12473

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Prof. Dr. Saiyang Zhang

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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

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Published Papers (7 papers)

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Research

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16 pages, 3927 KiB

Open AccessArticle

Activity of Potassium Channel BmK-NSPK Inhibitor Regulated by Basic Amino Acid Residues: Novel Insight into the Diverse Peptide Pharmacology

by Zheng Zuo, Xuhua Yang, Haozhen Zhang, Chenhu Qin, Zhijian Cao and Yingliang Wu

Molecules 2025, 30(3), 450; https://doi.org/10.3390/molecules30030450 - 21 Jan 2025

Viewed by 370

Abstract

The molecular interactions between venomous peptides and potassium channels have extensively enriched the knowledge of diverse peptide pharmacology, and the in-depth understanding of general features of the various peptide functions remains a formidable challenge. In this work, the role of peptide basic residues in peptide pharmacology was first investigated. Although the venomous BmK-NSPK peptide had the critically conserved functional residues occurring in its similar and potent potassium channel-inhibiting peptides, it was a remarkably weak inhibitor of potassium channels due to fewer basic residues. Additionally, 1 μM BmK-NSPK only inhibited 1.2 ± 1.0%, 1.7 ± 0.70%, 2.3 ± 0.49% and 5.4 ± 0.70% of hKv1.1, hKv1.2, hKv1.3 and hKv1.6 channel currents. The introduction of one or two basic residues in BmK-NSPK-I15K, BmK-NSPK-I18K, BmK-NSPK-I26K and BmK-NSPK-I18K/I26K could not improve BmK-NSPK activity. The modifications of more than three basic residues were found to continuously improve BmK-NSPK activity, and the corresponding BmK-NSPK-7K and BmK-NSPK-8K mutants could effectively inhibit hKv1.3 channel with IC₅₀ values of 2.04 ± 0.68 nM and 21.5 ± 1.99 nM, respectively. Also, 1 μM BmK-NSPK-7K and BmK-NSPK-8K mutants could inhibit 84.1 ± 7.0% and 84.3 ± 1.8% of hKv1.1 channel currents. In addition, BmK-NSPK-7K and BmK-NSPK-8K mutants were found to differentially inhibit hKv1.6 and chimeric hKv1.3 channels. These findings first highlight the critical role of basic residues in the activity of potassium channel peptide inhibitors and provide novel insight into the diverse peptide pharmacology. Full article

(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)

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14 pages, 3716 KiB

Open AccessArticle

Novel Inhibitors for MDM2-MDM4 E3 Ligase Potently Induce p53-Indepedent Apoptosis in Drug-Resistant Leukemic Cells

by Rati Lama, Joseph M. Fose, Diana Martín, Inés G. Muñoz, Eunice S. Wang, Pamela J. Sung, Sherry R. Chemler and Xinjiang Wang

Molecules 2025, 30(1), 186; https://doi.org/10.3390/molecules30010186 - 5 Jan 2025

Viewed by 850

Abstract

MDM2 and MDM4 are major negative regulators of tumor suppressor p53. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction. Inhibitors disrupting p53 interaction with MDM2/MDM4 are in clinical trials in patients bearing wild-type p53 cancers. However, these inhibitors are not designed to work for p53-null/mutant cancer cells. Owing to the importance of the E3 ligase of MDM2 in its p53-independent oncogenic activity, inhibitors targeting the E3 ligase activity of MDM2-MDM4 are desirable for p53-mutant cancer cells. Here, we report the development of such inhibitors with pro-apoptotic activity in p53-null leukemic cells. Among analogues of MDM2-MDM4 E3 ligase inhibitors, we initially identified MMRi36 as a potent pro-apoptotic compound in p53-null leukemic cells with acquired drug resistance. MMRi36 acts as an activator of MDM2-MDM4 E3 ligase by stabilizing MDM2-MDM4 heterodimers and promotes MDM2/MDM4 degradation in cells. Interestingly, replacement of the sulfur in 1,3,4-thiadiazole MMRi36 with a carbon led to identification of pyrazole MMRi36C that dissociates the MDM2-MDM4 RING heterodimers, inhibits the E3 ligase activity of the complex, and induces p53 protein accumulation, but retains the p53-independent pro-apoptotic activity. A brief SAR study identified a fluorine derivative of MMRi36C with improved pro-apoptotic activity. This study discovered a novel class of compound that targets MDM2-MDM4 ubiquitin E3 ligase activity for apoptosis induction in p53-mutant cancer cells. Full article

(This article belongs to the Special Issue Small-Molecule Inhibitors: Synthesis, Cytotoxicity and Biological Activities)

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13 pages, 455 KiB

Open AccessArticle

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

Cited by 2 | Viewed by 1722

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 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

Open AccessArticle

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 1643

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 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

Open AccessArticle

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 3109

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 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

Open AccessArticle

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 1949

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 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

Open AccessReview

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 3 | Viewed by 1778

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, 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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