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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.

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