Comparison of [17(20)E]-21-Norpregnene oxazolinyl and benzoxazolyl derivatives as inhibitors of CYP17A1 activity and prostate carcinoma cells growth


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Abstract

HIGHLIGHTSSynthesis of oxazolinyl and benzoxazolyl derivatives of [17(20)E]-21-norpregnene.Inhibition of CYP17A1 activity.Computational modeling of [17(20)E]-21-norpregnene oxazolinyl derivatives binding modes in CYP17A1 active site.Inhibition of prostate carcinoma PC-3 and LNCaP cells growth.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 3β-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.

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