RESUMO
We report here that pregnenolonyl-α-glucoside (2), a steryl glycoside synthesized directly from pregnenolone and glucose via a consecutive multienzyme-catalyzed process, exhibits marked dose-dependent cytotoxic activity against HT29, AGS, and ES-2 cells with IC50 values of 23.5 to 50.9 µM. An in vitro CYP17A1 binding pattern assay and protein-ligand docking model support that 2, like abiraterone, binds in the active site heme iron pocket of CYP17A1.
Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Glucosídeos/farmacologia , Pregnenolona/análogos & derivados , Pregnenolona/farmacologia , Androstenos/metabolismo , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bactérias/enzimologia , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Glucosídeos/síntese química , Glucosídeos/metabolismo , Glicosilação , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Pregnenolona/metabolismo , Ligação ProteicaRESUMO
Enzymatic glycosylation of sterols/steroids with glycosyltransferase HP0421 shows protein plasticity on generation of configurationally rare steryl-α-glucosides. Investigation of trans-androsteronyl-α-glucoside on tamoxifen-treated MCF-7 breast cancer cells shows dose-dependent depression of cell viability and enhanced drug effectiveness, illustrating a new avenue for the production of novel steryl-α-glucosides with useful biological activities.