Design, synthesis, biological evaluation and molecular docking of novel isatin-oxime ether derivatives as potential IDH1 inhibitors.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2025-01-02 DOI:10.1007/s11030-024-11084-4

Kangning Wei, Kaige Guo, Ye Tao, Xuanming Gong, Guobing Yan, Liangliang Wang, Ming Guo

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Abstract

A series of novel isatin-oxime ether derivatives were designed, synthesized and characterized by ¹H NMR and ¹³C NMR and HRMS. These compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (A549, HepG2 and Hela) by MTT assay. According to the experimental results, compounds 6a (IC₅₀ = 0.34μM), 6c (IC₅₀ = 14nM) and 6r (IC₅₀ = 45nM) were found as the excellent selectivity and high activity against A549, whereas compounds 6m (IC₅₀ = 12nM) and 6n (IC₅₀ = 25nM) displayed the significant activity for HepG2, respectively. Compound 6f (IC₅₀ = 30nM), 6n (IC₅₀ = 9nM) and 6o (IC₅₀ = 20nM) also showed the excellent activity against Hela. From the experiments of cell migration and colony formation assays, the findings demonstrated that 6m can effectively suppress the migration and growth of HepG2 cells. In addition, the results of molecular docking studies determined the strong binding interactions between the potential active compounds 6m and 6n and the active sites of isocitrate dehydrogenase 1 (IDH1) with the lowest binding affinity energy.

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新型isatin-肟醚类IDH1抑制剂的设计、合成、生物学评价及分子对接。

设计、合成了一系列新的异辛肟醚衍生物，并通过1H NMR、13C NMR和HRMS对其进行了表征。采用MTT法对3种人癌细胞（A549、HepG2和Hela）的体外细胞毒性进行了评价。实验结果表明，化合物6a （IC50 = 0.34μM）、6c （IC50 = 14nM）和6r （IC50 = 45nM）对A549具有较好的选择性和较高的活性，而化合物6m （IC50 = 12nM）和6n （IC50 = 25nM）对HepG2具有较强的活性。化合物6f （IC50 = 30nM）、6n （IC50 = 9nM）和60 （IC50 = 20nM）也表现出良好的抗Hela活性。通过细胞迁移实验和集落形成实验，发现6m能有效抑制HepG2细胞的迁移和生长。此外，分子对接研究结果确定了潜在活性化合物6m和6n与异柠檬酸脱氢酶1 （IDH1）活性位点之间具有较强的结合相互作用，结合亲和能最低。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;