Copper(I)-Catalyzed Nitrile-Addition/N-Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro‑6H‑indolo[3,2‑c]quinolin-6-ones as Potent Topoisomerase‑I Inhibitors

• Published in: Journal of medicinal chemistry Vol. 64; no. 3; pp. 1435 - 1453
• Main Authors: Hsueh, Wen-Yun, Lee, Ying-Shuan E, Huang, Min-Sian, Lai, Chin-Hung, Gao, Yu-Sheng, Lin, Jo-Chu, Chen, Yu-Fen, Chang, Chih-Lin, Chou, Shan-Yen, Chen, Shyh-Fong, Lu, Yann-Yu, Chang, Lien-Hsiang, Lin, Shu Fu, Lin, Yu-Hsiang, Hsu, Pi-Chen, Wei, Win-Yin, Huang, Ya-Chi, Kao, Yi-Feng, Teng, Li-Wei, Liu, Hung-Huang, Chen, Ying-Chou, Yuan, Ta-Tung, Chan, Ya-Wen, Huang, Po-Hsun, Chao, Yu-Ting, Huang, Shin-Yi, Jian, Bo-Han, Huang, Hsin-Yi, Yang, Sheng-Chuan, Lo, Tzu-Hao, Huang, Guan-Ru, Wang, Shao-Yun, Lin, Her-Sheng, Chuang, Shih-Hsien, Huang, Jiann-Jyh
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.02.2021; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00727

In this paper, we present a copper­(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo­[3,2-c]­quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)­acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis­[2-(dimethylamino)­ethyl]-5,12-dihydro-6H-[1,3]­dioxolo­[4′,5′:5,6]­indolo­[3,2-c]­quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top–DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo­[3,2-c]­quinolin-6-ones as topoisomerase-I inhibitors.