title: Novel oxazolinyl derivatives of pregna-5,17(20)-diene as 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitors.
abstract: New oxazolinyl derivatives of [17(20)E]-pregna-5,17(20)-diene: 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4',5'-dihydro-1',3'-oxazole 1 and 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]methyl}-4',4'-dimethyl-4',5'-dihydro-1',3'-oxazole 2 were evaluated as potential CYP17A1 inhibitors in comparison with 17-(pyridin-3-yl)androsta-5,16-dien-3β-ol 3 (abiraterone). Differential absorption spectra of human recombinant CYP17A1 in the presence of compound 1 (λmax=422 nm, λmin=386 nm) and compound 2 (λmax=416 nm) indicated significant differences in enzyme/inhibitors complexes. CYP17A1 activity was measured using electrochemical methods. Inhibitory activity of compound 1 was comparable with abiraterone 3 (IC50=0.9±0.1 μM, and IC50=1.3±0.1 μM, for compounds 1 and 3, respectively), while compound 2 was found to be weaker inhibitor (IC50=13±1 μM). Docking of aforementioned compounds to CYP17A1 revealed that steroid fragments of compound 1 and abiraterone 3 occupied close positions; oxazoline cycle of compound 1 was coordinated with heme iron similarly to pyridine cycle of abiraterone 3. Configuration of substituents at 17(20) double bond in preferred docked position corresponded to Z-isomers of compounds 1 and 2. Presence of 4'-substituents in oxazoline ring of compound 2 prevents coordination of oxazoline nitrogen with heme iron and worsens its docking score in comparison with compound 1. These data indicate that oxazolinyl derivative of [17(20)E]-pregna-5,17(20)-diene 1 (rather than 4',4'-dimethyl derivative 2) may be considered as potential CYP17A1 inhibitor and template for development of new compounds affecting growth and proliferation of prostate cancer cells.
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Alexey V
authors: AV
authors: Kuzikov
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Nikita O
authors: NO
authors: Dugin
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Sergey V
authors: SV
authors: Stulov
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Dmitry S
authors: DS
authors: Shcherbinin
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Maria S
authors: MS
authors: Zharkova
authors: Engelhardt Institute of Molecular Biology RAS, Moscow, Russia.
authors: Yaroslav V
authors: YV
authors: Tkachev
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 RAMS, Moscow, Russia.
authors: Alexander V
authors: AV
authors: Veselovsky
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Victoria V
authors: VV
authors: Shumyantseva
authors: Orekhovich Institute of Biomedical Chemistry RAMS, Moscow, Russia.
authors: Alexander Y
authors: AY
authors: Misharin
mesh_terms: D001665:Binding Sites; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004563:Electrochemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000737:chemistry*; D011278:Pregnanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D008024:Ligands; D010080:Oxazoles; D011278:Pregnanes; D013254:Steroid 17-alpha-Hydroxylase
keywords: Absorption spectra; CYP17A1 inhibitors; Electrochemistry; Molecular modeling; Oxazolinyl derivatives of pregna-5,17(20)-diene