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

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.

Synthesis of Isocryptolepine‐Triazole Adducts and Evaluation of Their Cytotoxic Activity

“…Eighteen isocryptolepine-triazole analogs (11 a-11 r) were prepared to evaluate for their cytotoxic activities. [30][31][32][33][34][35][36][37] In vitro cytotoxic evaluation…”

Copper‐Catalyzed C(sp2)−N Coupling of (E)‐3‐(2‐Bromophenysl)‐2‐arylacrylamides for the Synthesis of 3‐Arylquinolin‐2‐ones

“…It was worth mentioning that substrates 1 g , 1 p , 1 aa bearing a nitro group were also feasible in this reaction and provided the desired products 2 g , 2 p , 2 aa in 69 %, 59 %, 53 % yields respectively. These results indicated that the possible interaction of nitro group with Cu(I) intermediates did not show any detrimental effect to this transformation [25a–b] . Furthermore, multi‐functionalized substrates containing dibromo, dimethoxyl and trimethoxyl groups were workable under the standard conditions, giving the desired products 2 t , 2 u , 2 v , 2 w in 46 %–79 % yields.…”

Discovery of a DNA Topoisomerase I Inhibitor Huanglongmycin N and Its Congeners from Streptomyces sp. CB09001

“…The interaction of 14 with the top1–DNA complex was next revealed by a docking simulation on a top1–DNA–drug ternary complex (PDB 1TL8) using HCPT and 1 as controls (Figures E and S12). The poses of 14 and HCPT with the lowest energy in the complex were identified and were similarly stacked in the DNA cleavage site formed by the TPC11–G112 and T10–A113 base pairs, with a likely π–π stacking interaction formed through its anthraquinone ring. The C-9 carbonyl group in 14 may serve as a hydrogen bond acceptor for Arg364, while its ethyl side chain interacts with Thr718 through certain hydrophobic interactions.…”