ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Glucosides/pharmacology , Pregnenolone/analogs & derivatives , Pregnenolone/pharmacology , Androstenes/metabolism , Androstenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Bacteria/enzymology , Catalytic Domain , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme Inhibitors/metabolism , Glucosides/chemical synthesis , Glucosides/metabolism , Glycosylation , HEK293 Cells , Humans , Molecular Docking Simulation , Pregnenolone/metabolism , Protein BindingABSTRACT
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.
