Jielin Tang , Yuxin Zhang , Lingling Zhou , Xiangrui Song , Yusi Wei , Ji Qi , Jianmin Wu , Zengqiang Song , Lingling Zhan
{"title":"Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer","authors":"Jielin Tang , Yuxin Zhang , Lingling Zhou , Xiangrui Song , Yusi Wei , Ji Qi , Jianmin Wu , Zengqiang Song , Lingling Zhan","doi":"10.1016/j.bmc.2024.117786","DOIUrl":null,"url":null,"abstract":"<div><p>An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound <strong>3ab</strong> showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that <strong>3ab</strong> could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and apoptosis. Mechanistic studies revealed that compound <strong>3ab</strong> inhibited the proliferation of CRC cells via suppressing the AKT/GSK-3β pathway. <em>In vivo</em> evaluation demonstrated remarkable antitumor effect of <strong>3ab</strong> (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate <strong>3ab</strong> could be considered as a potential CRC therapy agent for further development.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-01","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/S0968089624002001","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
An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound 3ab showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that 3ab could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and apoptosis. Mechanistic studies revealed that compound 3ab inhibited the proliferation of CRC cells via suppressing the AKT/GSK-3β pathway. In vivo evaluation demonstrated remarkable antitumor effect of 3ab (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate 3ab could be considered as a potential CRC therapy agent for further development.
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.