Details

Autor(en) / Beteiligte

• Zolottsev, Vladimir A.
• Tkachev, Yaroslav V.
• Latysheva, Alexandra S.
• Kostin, Vladimir A.
• Novikov, Roman A.
• Timofeev, Vladimir P.
• Morozevich, Galina E.
• Kuzikov, Alexey V.
• Shumyantseva, Victoria V.
• Misharin, Alexander Y.

Titel

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

Ist Teil von

• Steroids, 2018-01, Vol.129, p.24-34

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •Synthesis 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.