New D-modified androstane derivatives as aromatase inhibitors☆
| Autor: | Ljubica D. Medić Mijačević, Radmila Kovacevic, Evgenija A. Djurendić, Srdjan Z. Stojanović, Silvana A. Andric, Katarina M. Penov Gaši, Slobodanka Stanković, Dora Molnar Gabor, Marija N. Sakač, János Csanádi, Otto N. Arcson |
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| Rok vydání: | 2001 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Stereochemistry Clinical Biochemistry Oppenauer oxidation Crystallography X-Ray Binding Competitive Biochemistry Chemical synthesis Inhibitory Concentration 50 chemistry.chemical_compound Hydrolysis Endocrinology Benzoquinones medicine Animals Rats Wistar Molecular Biology IC50 Pharmacology Degree of unsaturation biology Aromatase Inhibitors Organic Chemistry Rats Kinetics chemistry Enzyme inhibitor biology.protein Female Androstane Androstanes Aminoglutethimide medicine.drug |
| Zdroj: | Steroids. 66:645-653 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/s0039-128x(01)00096-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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