RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Cobre/química , Nitrilos/química , Quinolonas/síntesis química , Quinolonas/farmacología , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacología , Animales , Catálisis , ADN-Topoisomerasas de Tipo I/química , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Quinolonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of selenophene derivatives 3 were synthesized as potential CHK1 inhibitors. The effects of substitution on the 4'- or 5'-position of selenophene moiety and shifting the hydroxyl group position on C6- phenolic ring of oxindole were explored. This study led to the discovery of the most potent CHK1 inhibitors 29-33 and 39-43, which had IC(50) values in the subnanomolar range.