Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity

Abstract Five 4,5-dihydro-1,3-oxazole derivatives of [17(20) E ]-21-norpregnene, comprising 3β-hydroxy-5-ene ( 1 ), 3,6-dioxo-4-ene ( 2 ), 3-oxo-4-ene ( 3 ), 3α,5α-cyclo-6-oxo ( 4 ), 3β-hydroxy-6-oxo ( 5 ) fragments were synthesized. Synthesis was conducted with improved procedure, based on reaction of suitably protected [17(20) E ]-pregnen-21-oic acids with ethanolamine in presence of triphenyl phosphine, carbon tetrachloride, and triethyl amine. Potency of the compounds 1 – 5 to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity was studied by highly sensitive electrochemical method, using the enzyme immobilization technique. Compounds 1 and 3 were found to be potent CYP17A1 inhibitors, compounds 2 and 5 were not active, compound 4 strongly and irreversibly suppressed the enzyme activity. Molecular docking of compounds 1 – 5 in the active site of CYP17A1 showed that positions of all compounds in the enzyme active site were similar.