Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-10-02 DOI:10.1007/s11030-024-10998-3

Tianyu Xie, Wenbo Hu, Lin You, Xin Wang

{"title":"Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors.","authors":"Tianyu Xie, Wenbo Hu, Lin You, Xin Wang","doi":"10.1007/s11030-024-10998-3","DOIUrl":null,"url":null,"abstract":"With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-024-10998-3","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}

引用次数: 0

Abstract

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC₅₀ values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

查看原文本刊更多论文

作为 c-Met 激酶抑制剂的噻吩吡啶衍生物的设计、合成和生物学评价。

以卡博替尼为前体，设计、合成并评估了以噻吩并[2,3-b]吡啶为支架的新型小分子 c-Met 激酶抑制剂对 A549、Hela 和 MCF-7 细胞系的生物活性。以卡博替尼为对照药物，采用 MTT 法测试了 16 种化合物的体外活性。大多数化合物对细胞具有中等到较强的抑制活性。其中，化合物 10 的抑制活性最强，优于先导化合物卡博替尼。它对 A549、Hela 和 MCF-7 细胞的 IC50 值分别为 0.005、2.833 和 13.581 μM。菌落形成试验表明，化合物 10 能明显抑制 A549 细胞的菌落形成，并以浓度依赖性的方式抑制其生长。伤口愈合试验表明，与空白对照组相比，化合物 10 能有效抑制癌细胞的迁移。AO/EB 试验表明，化合物 10 能以浓度依赖性方式有效诱导细胞凋亡。基本结构-活性关系、分子对接和药代动力学研究揭示了噻吩并[2,3-b]吡啶衍生物在抗肿瘤活性中的重要作用。

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

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;