title: New D-modified androstane derivatives as aromatase inhibitors.
abstract: Starting from a 16-oximino derivative of 5-androstene the newly-synthesized 16-oximino-17-hydroxy-17-substituted derivatives 2-4 gave by the Beckmann fragmentation reaction the corresponding D-seco derivatives 6-9. Besides, in the case of the 17-hydroxy-17-methyl-16-oximino derivative 2, as a result of the rearrangement, the hydrolysis product 5 of the 16-oximino group with the opposite configuration at the C-17 was obtained. By the Oppenauer oxidation and/or by dehydration of 7 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), the corresponding derivatives 12, 13, and 14 were obtained. The structures of 6 and 12 were unambiguously proved by the appropriate X-ray structural analysis. Kinetic analysis for anti-aromatase activity showed that compound 12 expressed the highest inhibition in the denucleated rat ovarian fraction in comparison to other androstene derivatives (IC(50) was 0.42 microM). In comparison to aminoglutethimide (AG) activity, it was 3.5 times lower. The inhibition was competitive, with K(i) of 0.27 microM. Introduction of additional units of unsaturation (compounds 13 and 14) in D-seco derivatives did not increase anti-aromatase activity.
authors: Institute of Chemistry, Faculty of Sciences, University of Novi Sad, 21000 Novi Sad, Trg Dositeja Obradovića 3, Yugoslavia. sazvon@eunet.yu
authors: K M
authors: KM
authors: Penov Gasi
authors: S M
authors: SM
authors: Stanković
authors: J J
authors: JJ
authors: Csanádi
authors: E A
authors: EA
authors: Djurendić
authors: M N
authors: MN
authors: Sakac
authors: L
authors: L
authors: Medić Mijacević
authors: O N
authors: ON
authors: Arcson
authors: S Z
authors: SZ
authors: Stojanović
authors: S
authors: S
authors: Andrić
authors: D
authors: D
authors: Molnar Gabor
authors: R
authors: R
authors: Kovacević
mesh_terms: D000731:Androstanes / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D047072:Aromatase Inhibitors; D016227:Benzoquinones / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005260:Female; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000731:Androstanes; D047072:Aromatase Inhibitors; D016227:Benzoquinones; C000928:dichlorodicyanobenzoquinone