RESUMEN
Four new 4,5-dihydro-1,3-oxazole, and four new benzo-[d]-oxazole derivatives of [17(20)E]-21-norpregnene, differing in the structure of steroid moiety, were synthesized and evaluated for their potency to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity. Among new compounds, the only oxazolinyl derivative comprising 5-oxo-4,5-seco-3-yn- moiety potently inhibited CYP17A1. Binding modes of the oxazolinyl derivatives of [17(20)E]-21-norpregnene were analyzed by molecular dynamics simulations, and model of alternate, water-bridged type II interaction was proposed for these compounds. Eight new compounds, together with two CYP17A1-inhibiting oxazolinyl derivatives synthesized earlier, abiraterone and galeterone were evaluated for their potency to inhibit prostate carcinoma PC-3 and LNCaP cells growth. Oxazolinyl and benzoxazolyl derivatives comprising 3ß-hydroxy-5-ene moieties potently inhibited prostate carcinoma cell growth; inhibitory potencies of 3-oxo-4-en- and 5-oxo-4,5-seco-3-yn- derivatives were significantly lower.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Norpregnenos/química , Oxazoles/química , Oxazoles/farmacología , Neoplasias de la Próstata/patología , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Benzoxazoles/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Electroquímica , Humanos , Masculino , Simulación del Acoplamiento Molecular , Oxazoles/metabolismo , Conformación Proteica , Esteroide 17-alfa-Hidroxilasa/química , Esteroide 17-alfa-Hidroxilasa/metabolismoRESUMEN
Five 4,5-dihydro-1,3-oxazole derivatives of [17(20)E]-21-norpregnene, comprising 3ß-hydroxy-5-ene (1), 3,6-dioxo-4-ene (2), 3-oxo-4-ene (3), 3α,5α-cyclo-6-oxo (4), 3ß-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.
