title: Synthesis of hydroxy derivatives of highly potent non-steroidal CYP 17 inhibitors as potential metabolites and evaluation of their activity by a non cellular assay using recombinant human enzyme.
abstract: Inhibition of CYP 17 is a promising strategy for the treatment of prostate cancer. Recently two non-steroidal compounds with high in vitro activity were synthesized in our group (BW19 and BW95). However, after a few hours they showed in vivo a strong decrease in their activity. This might be due to a fast biodegradation. Potential hydroxy and epoxy metabolites were synthesized and their inhibitory activities were tested by a new non-cellular assay using recombinant enzyme. As source, membrane fractions of E. coli pJL17/OR coexpressing human CYP 17 and rat NADPH-P450-reductase were, used. Showing a high and constant CYP 17 activity and a fast and easy isolation procedure the new method was advantageous compared with the microsomal assay. Interestingly, all the new synthesized hydroxy and epoxy compounds except one showed a lower inhibition of CYP 17 than the parent compounds. Thus, the loss of in vivo activity may be partly explained.
authors.affiliation: 8.5 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Tilman U
authors.initials: TU
authors.lastname: Hutschenreuter
authors.forename: Peter B
authors.initials: PB
authors.lastname: Ehmer
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007928:Lethal Dose 50; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D011994:Recombinant Proteins; D013739:Testosterone; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D013254:Steroid 17-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase