Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors

Abstract New oxazolinyl derivatives of [17(20) E ]-pregna-5,17(20)-diene: 2′-{[( E )-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4′,5′-dihydro-1′,3′-oxazole 1 and 2′-{[( E )-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4′,4′-dimethyl-4′,5′-dihydro-1′,3′-oxazole 2 were evaluated as potential CYP17A1 inhibitors in comparison with 17-(pyridin-3-yl)androsta-5,16-dien-3β-ol 3 (abiraterone). Differential absorption spectra of human recombinant CYP17A1 in the presence of compound 1 ( λ max  = 422 nm, λ min  = 386 nm) and compound 2 ( λ max  = 416 nm) indicated significant differences in enzyme/inhibitors complexes. CYP17A1 activity was measured using electrochemical methods. Inhibitory activity of compound 1 was comparable with abiraterone 3 (IC 50  = 0.9 ± 0.1 μM, and IC 50  = 1.3 ± 0.1 μM, for compounds 1 and 3 , respectively), while compound 2 was found to be weaker inhibitor (IC 50  = 13 ± 1 μM). Docking of aforementioned compounds to CYP17A1 revealed that steroid fragments of compound 1 and abiraterone 3 occupied close positions; oxazoline cycle of compound 1 was coordinated with heme iron similarly to pyridine cycle of abiraterone 3 . Configuration of substituents at 17(20) double bond in preferred docked position corresponded to Z -isomers of compounds 1 and 2 . Presence of 4′-substituents in oxazoline ring of compound 2 prevents coordination of oxazoline nitrogen with heme iron and worsens its docking score in comparison with compound 1 . These data indicate that oxazolinyl derivative of [17(20) E ]-pregna-5,17(20)-diene 1 (rather than 4′,4′-dimethyl derivative 2 ) may be considered as potential CYP17A1 inhibitor and template for development of new compounds affecting growth and proliferation of prostate cancer cells.