Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer

• Published in: Bioorganic & medicinal chemistry Vol. 108; pp. 117786 - 117799
• Main Authors: Tang, Jielin, Zhang, Yuxin, Zhou, Lingling, Song, Xiangrui, Wei, Yusi, Qi, Ji, Wu, Jianmin, Song, Zengqiang, Zhan, Lingling
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2024; Elsevier
• Subjects: AKT/GSK-3β; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Apoptosis - drug effects; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Efficient synthesis; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Indoline-maleimide conjugates; Life Sciences & Biomedicine; Maleimides - chemical synthesis; Maleimides - chemistry; Maleimides - pharmacology; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; PBS; Na2CO3; [RhCpCl2]2; AKT/GSK-3β; HFIP; Colorectal cancer; 1H NMR; 13C NMR; MTS; Indoline-maleimide conjugates; HRMS; CRC; Antitumor; PI; Efficient synthesis; Rh(III); Cu(OTf)2; HPLC; 5-Fu; AKT/GSK-3 beta; PATHWAY; INHIBITORS; BREAST
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117786

[Display omitted] •Thirty four novel type of indoline-maleimide conjugates were efficiently synthesized using the newly developed method.•Indoline-maleimide conjugate 3ab showed better effect than 5-Fu against several CRC cells and nontumor colon cell.•Indoline-maleimide conjugate 3ab exhibited a significant inhibitory effect in HCT116 tumor xenograft models compared with 5-Fu, and showed remarkable in vivo safety profile.•Indoline-maleimide conjugate 3ab inhibited the proliferation of CRC cells by suppressing the AKT/GSK-3β pathway.•Indoline-maleimide conjugate 3ab has been demonstrated as a potential CRC therapy agent for further development. 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.