An N-linked imidazo[1,2-a]pyridine benzoheterobicyclic hybrid inhibits mitosis and cancer cell proliferation by targeting tubulin

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-05-15 DOI:10.1016/j.bmc.2025.118242

Tuhin Sarkar , Mehak Sood , Shweta Shyam Prassanawar , Kousar Jahan , Aaditi Kulkarni , Rushikesh Ahirkar , Parteek Prasher , Prasad V. Bharatam , Dulal Panda

{"title":"An N-linked imidazo[1,2-a]pyridine benzoheterobicyclic hybrid inhibits mitosis and cancer cell proliferation by targeting tubulin","authors":"Tuhin Sarkar , Mehak Sood , Shweta Shyam Prassanawar , Kousar Jahan , Aaditi Kulkarni , Rushikesh Ahirkar , Parteek Prasher , Prasad V. Bharatam , Dulal Panda","doi":"10.1016/j.bmc.2025.118242","DOIUrl":null,"url":null,"abstract":"<div><div>Colchicine-site agents have strong potential to be used as tubulin-targeted anticancer agents. In this study, a series of imidazo[1,2-a]pyridine-benzoheterobicyclic hybrids linked by a nitrogen atom as N-heterocyclic imines were designed as colchicine site binding agents. Cell-based assays identified two compounds, 6b (N-(3-(4-chlorophenyl)imidazo[1,2-a](pyridin-2-yl)benzo[d]thiazol-2(3H)-imine) and 6c (N-(6-chloro-3-phenylimidazo[1,2-a]pyridin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine), as the most potent antiproliferative compounds against cervical cancer (HeLa) cells. Compound 6c inhibited purified tubulin polymerization in vitro and depolymerized microtubules in HeLa and MCF-7 cells. Additionally, 6c arrested HeLa cells in the mitotic phase, increased the production of reactive oxygen species, and induced cell death. The compound also exhibited a strong binding affinity towards the colchicine binding site on tubulin. Quantum chemical analysis and molecular docking indicated that 6c preferentially binds to tubulin in its iminic tautomeric state. The chemoinformatic analysis further revealed that 6c occupies a unique and therapeutically relevant chemical space with a favorable profile regarding physicochemical properties, ADMET, and pharmacokinetics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"128 ","pages":"Article 118242"},"PeriodicalIF":3.3000,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096808962500183X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Colchicine-site agents have strong potential to be used as tubulin-targeted anticancer agents. In this study, a series of imidazo[1,2-a]pyridine-benzoheterobicyclic hybrids linked by a nitrogen atom as N-heterocyclic imines were designed as colchicine site binding agents. Cell-based assays identified two compounds, 6b (N-(3-(4-chlorophenyl)imidazo[1,2-a](pyridin-2-yl)benzo[d]thiazol-2(3H)-imine) and 6c (N-(6-chloro-3-phenylimidazo[1,2-a]pyridin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine), as the most potent antiproliferative compounds against cervical cancer (HeLa) cells. Compound 6c inhibited purified tubulin polymerization in vitro and depolymerized microtubules in HeLa and MCF-7 cells. Additionally, 6c arrested HeLa cells in the mitotic phase, increased the production of reactive oxygen species, and induced cell death. The compound also exhibited a strong binding affinity towards the colchicine binding site on tubulin. Quantum chemical analysis and molecular docking indicated that 6c preferentially binds to tubulin in its iminic tautomeric state. The chemoinformatic analysis further revealed that 6c occupies a unique and therapeutically relevant chemical space with a favorable profile regarding physicochemical properties, ADMET, and pharmacokinetics.

查看原文本刊更多论文

n -连接咪唑[1,2-a]吡啶苯并杂环杂环化合物通过靶向微管蛋白抑制有丝分裂和癌细胞增殖

秋水仙碱类药物具有作为微管蛋白靶向抗癌药物的巨大潜力。本研究设计了一系列由氮原子连接的咪唑[1,2-a]吡啶-苯并杂环杂环化合物作为秋水仙碱位点结合剂。以细胞为基础的实验鉴定了两种化合物6b (N-（3-（4-氯苯基）咪唑[1,2-a]（吡啶-2-基）苯并[d]噻唑-2(3H)-亚胺）和6c （N-（6-氯-3-苯并咪唑[1,2-a]吡啶-2-基）-1,3-二氢- 2h -苯并[d]咪唑-2-亚胺）是对宫颈癌（HeLa）细胞最有效的抗增殖化合物。化合物6c在体外抑制纯化微管蛋白聚合，并在HeLa和MCF-7细胞中抑制微管解聚。此外，6c在有丝分裂期阻滞HeLa细胞，增加活性氧的产生，并诱导细胞死亡。该化合物对秋水仙碱在微管蛋白上的结合位点也表现出很强的结合亲和力。量子化学分析和分子对接表明，6c优先与亚胺互变异构状态的微管蛋白结合。化学信息学分析进一步表明，6c占据了一个独特的、与治疗相关的化学空间，在理化性质、ADMET和药代动力学方面具有良好的特征。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.