alexa 20-amino and 20,21-aziridinyl pregnene steroids: development of potent inhibitors of 17 alpha-hydroxylase C17,20-lyase (P450 17).
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Clinical & Experimental Pharmacology

Author(s): Njar VC, Hector M, Hartmann RW

Abstract Share this page

Abstract In the search for potent inhibitors of P450 17, the key enzyme of androgen biosynthesis, the 20,21-aziridinyl- and 20-aminopregnene steroids 1-11 were synthesized and tested toward rat testicular P450 17. Only the aziridinyl-substituted pregnenolones (1 and 2) and progesterones (3 and 4), respectively, showed inhibitory activity, which strongly depends on C20 stereochemistry. The most active compound 1 [20(S)-20,21-aziridinylpregn-5-en-3 beta-ol; IC50 0.21 microM, progesterone 25 microM; Ki = 1.7 nM, K(m) progesterone = 7.0 microM] is the strongest inhibitor of rat P450 17 described so far. Using UV-vis difference spectroscopy, complexation of the aziridinyl nitrogen to the heme iron, Fe3+, of P450 17 was observed, which could not be reversed by high concentrations of substrate. Preincubation of the enzyme with 1 in the absence and presence of NADPH followed by charcoal treatment results in a strong decrease of enzyme activity within 30 s. However, a recovery of enzyme activity was observed: 90 min after charcoal treatment 75\% of the activity was restored.
This article was published in Bioorg Med Chem and referenced in Journal of Clinical & Experimental Pharmacology

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

Relevant Topics

Peer Reviewed Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version