In this paper, we present a copper(I)-catalyzed nitrile-addition/ -arylation ring-closure cascade for the synthesis of 5,11-dihydro-6 -indolo3,2- quinolin-6-ones from 2-(2-bromophenyl)- -(2-cyanophenyl)acetamides. Using CuBr and -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-bis2-(dimethylamino)ethyl-5,12-dihydro-6 -1,3dioxolo4',5':5,6indolo3,2- quinolin-6-one ( ), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 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 with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6 -indolo3,2- quinolin-6-ones as topoisomerase-I inhibitors.