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

Abstract

In this paper, we present a copper(I)-catalyzed nitrile-addition/<i>N</i>-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6<i>H</i>-indolo[3,2-<i>c</i>]quinolin-6-ones from 2-(2-bromophenyl)-<i>N</i>-(2-cyanophenyl)acetamides. Using CuBr and <i>t</i>-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-6<i>H</i>-[1,3]dioxolo[4',5':5,6]indolo[3,2-<i>c</i>]quinolin-6-one (<b>2k</b>), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound <b>2k</b> 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 <b>2k</b> with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6<i>H</i>-indolo[3,2-<i>c</i>]quinolin-6-ones as topoisomerase-I inhibitors.