Copper(I)-Catalyzed Nitrile-Addition/<i>N</i>-Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6<i>H</i>-indolo[3,2-<i>c</i>]quinolin-6-ones as Potent Topoisomerase-I Inhibitors
Wen-Yun Hsueh, Ying-Shuan E. Lee, Min-Sian Huang, Chin‐Hung Lai, Yusheng Gao, Jo-Chu Lin, Yu‐Fen Chen, Chih-Lin Chang, Shan‐Yen Chou, Shyh‐Fong Chen, Yann‐Yu Lu, Lien-Hsiang Chang, Shu Lin, Yu‐Hsiang Lin, Pi-Chen Hsu, Win‐Yin Wei, Ya‐Chi Huang, Yi-Feng Kao, Li-Wei Teng, Hung-Huang Liu, Ying‐Chou Chen, Ta-Tung Yuan, Ya-Wen Chan, Po‐Hsun Huang, Yu-Ting Chao, Shin‐Yi Huang, Bo-Han Jian, Hsin‐Yi Huang, Sheng‐Chuan Yang, Tzu-Hao Lo, Guan-Ru Huang, Shaoyun Wang, Her-Sheng Lin, Shih‐Hsien Chuang, Jiann‐Jyh Huang
Abstract
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.