1. Synthesis and biochemical studies of 16- or 19-substituted androst-4-enes as aromatase inhibitors
- Author
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Kumiko Hoshi, Hiroki Kigawa, Etsushi Ishikawa, Mariko Oshibe, Ayako Mutsumi, and Mitsuteru Numazawa
- Subjects
Chemical Phenomena ,Stereochemistry ,Placenta ,medicine.medical_treatment ,Primary alcohol ,Steroid ,Structure-Activity Relationship ,Aromatase ,Non-competitive inhibition ,Drug Discovery ,medicine ,Humans ,chemistry.chemical_classification ,Androstenols ,Binding Sites ,Molecular Structure ,biology ,Aromatase Inhibitors ,Chemistry ,Biological activity ,Oxygen ,Kinetics ,Enzyme ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Microsome ,Molecular Medicine ,Androstenes ,Female ,NADP - Abstract
Androst-4-en-17-one derivatives [19-acetoxide 4, 16-bromides 14 and 15, 19,19-difluoride 18, and (19R,S)-19-acetylenic alcohol 25] and androst-4-en-17 beta-ol derivatives 3, 5, 10, 12, and 19 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All the 17-oxo steroids, except compound 25 and 17,19-diol 3 of this series, were effective competitive inhibitors with apparent Ki's ranging from 170 to 455 nM. 19,19-Difluoro steroid 18 and 19-acetylenic alcohol 25, a weak competitive inhibitor (Ki = 7.75 microM), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with kinact's of 0.0213 and 0.1053 min-1 for compounds 18 and 25, respectively. NADPH and oxygen were required for the time-dependent inactivation, and the substrate, androst-4-ene-3,17-dione, prevented it, but a nucleophile, L-cysteine, did not in each case. The results strongly suggest that aromatase would attack the 19-carbon of steroids 18 and 25.
- Published
- 1991
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