1 research outputs found
NâPhenylâ1,2,3,4âtetrahydroisoquinoline:an alternative scaffold for design of 17βâhydroxysteroid dehydrogenase 1 inhibitors
17βâHydroxysteroid dehydrogenases act at the preâreceptor level, catalysing interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less active estrone to estradiol and inhibitors have therapeutic potential in estrogenâdependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N âphenylâ1,2,3,4âtetrahydroisoquinoline (THIQ) template in all three ring systems was pursued using PomeranzâFritschâBobbitt, PictetâSpengler and BischlerâNapieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structureâactivity relationships are discussed. THIQs possessing a 6âhydroxyl group, lipophilic substitutions at the 1â or 4â positions in combination with N â4â˛âchlorophenyl substitution were most favourable for activity. Of these, racemic 41c had an IC 50 of ca. 350 nM, testifying to the applicability of this novel approach