Synthesis and in vitro evaluation of benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives as anticancer agents targeting the RhoA/ROCK pathway.

IF 5.6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2024-09-11 DOI:10.1080/14756366.2024.2390911

Jinhao Liang,Jin Huang,Jianzhan Yang,Weihong Liang,Haoxiang Li,Yunshan Wu,Bo Liu

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引用次数: 0

Abstract

Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.

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苯并[b]噻吩-3-羧酸 1,1-二氧化物衍生物作为靶向 RhoA/ROCK 通路的抗癌剂的合成和体外评估。

Rho 家族 GTP 酶调控细胞过程，促进肿瘤生长和转移；因此，RhoA 是抑制肿瘤转移的潜在靶点。然而，RhoA 靶向抗癌药物的开发进展有限。在此，我们合成了苯并[b]噻吩-3-羧酸 1,1-二氧化物衍生物，该衍生物基于我们之前研究中报道的 RhoA 共价抑制剂（DC-Rhoin）。观察到的结构-活性关系（C-3 中的羧酰胺和 C-5 中的 1-甲基-1H-吡唑）增强了衍生物的抗增殖活性。化合物 b19 能明显抑制 MDA-MB-231 细胞的增殖、迁移和侵袭，并促进其凋亡。抑制肌球蛋白轻链磷酸化和应力纤维的形成证实了 b19 通过 RhoA/ROCK 途径发挥抑制活性。这项研究为开发针对 RhoA/ROCK 通路的抗癌药物提供了参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.