title: 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.
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Vladimir A
authors: VA
authors: Kostin
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Vladimir A
authors: VA
authors: Zolottsev
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Alexey V
authors: AV
authors: Kuzikov
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Rami A
authors: RA
authors: Masamrekh
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Victoria V
authors: VV
authors: Shumyantseva
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Alexander V
authors: AV
authors: Veselovsky
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Sergey V
authors: SV
authors: Stulov
authors: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.
authors: Roman A
authors: RA
authors: Novikov
authors: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia. Electronic address: tim@eimb.ru.
authors: Vladimir P
authors: VP
authors: Timofeev
authors: Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
authors: Alexander Y
authors: AY
authors: Misharin
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: CYP17A1 inhibitors; Electrochemistry; Molecular modeling; Oxazolinyl derivatives of [17(20)E]-21-norpregnene; Structure-activity relationships; Synthesis