Synthesis and Biochemical Studies of 16- or 19-Substituted Androst-4-enes as Aromatase Inhibitors

Article abstract of DOI:10.1021/jm00112a028

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-17β-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 μM), caused a time-dependent, pseudo-first-order inactivation of aromatase activity with k_inact'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.