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
The strength of five working muscle groups of the lower arms of 8 male fencers, including adductor pollicis, extensor carpi radialis, flexor carpi radialis, extensor carpi ulnaris, and flexor carpi ulnaris, were examined during competition. Root mean square values of muscular electromyographic signals indicated that the shape of foil handles significantly influenced distribution of working strength of each muscle group. Use of the Pistol-Viscounti type of foil handle showed better distribution of strength among the 5 muscle groups than did other types of foils. Using the Pistol-Viscounti foil handle not only reduced muscular fatigue but also lessened cumulative trauma symptoms while holding a foil for a long duration.
