RESUMEN
The recent discovery of c-Jun NH2-terminal kinase JNK1 suppression by natural quercetagetin (1) is a promising lead for the development of novel anticancer agents. Using both X-ray structure and docking analyses we predicted that 5'-hydroxy- (2) and 5'-hydroxymethyl-quercetagetin (3) would inhibit JNK1 more actively than the parent compound 1. Notably, our drug design was based on the active enzyme-ligand complex as opposed to the enzyme's relatively open apo structure. In this paper we test our theoretical predictions, aided by docking-model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3. As calculated, both compounds strongly suppress JNK1 activity. The IC50 values were determined to be 3.4â µM and 12.2â µM, respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC50 =4.6â µM). Compound 2 was also shown to suppress matrix metalloproteinase-1 expression with high specificity after UV irradiation.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cromonas/química , Cromonas/farmacología , Proteína Quinasa 8 Activada por Mitógenos/química , Factores Biológicos , Cromonas/metabolismo , Diseño de Fármacos , Flavonas , Humanos , Concentración 50 Inhibidora , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Rayos UltravioletaRESUMEN
1,4-Benzoxazin-3-one is a scaffold which is found in a variety of biologically active molecules. Because of its unique structure and drug-like activities, 1,4-benzoxazin-3-ones have been widely used in drug discovery. However, just a few methods have been developed to access these molecules by catalytic asymmetric synthesis. We report herein the phase-transfer-catalysed asymmetric alkylation of 2-aryl-1,4-benzoxazin-3-ones as a new way for the highly enantioselective synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.