Synthesis of novel 21-trifluoropregnane steroids: inhibitors of 17 alpha-hydroxylase/17,20-lyase (17 alpha-lyase).
Novel 21-trifluoropregnenolone (6), 21-trifluoroprogesterone (7) and related compounds 4a and 8 have been synthesized in high yields from 3 beta-acetoxyandrost-5-ene-17 beta-carbaldehyde (3). The key reaction was the conversion of 3 into the 21-trifluoromethyl-20-alcohol as a diastereomeric mixture (4) by trifluoromethyltrimethylsilane (TMS-CF3) in the presence of tetrabutylammonium fluoride (TBAF). All compounds, including 6 and 7, were unambiguously characterized by IR, 1H and 19F NMR, high-resolution mass spectrometry (HRMS), and elemental analysis. On this basis, we concluded that the only report of an earlier synthesis of 6 and 7 is erroneous. Enzyme inhibition studies showed that 20 xi-hydroxy-21-trifluoropregn-4-en-3-one (8) is a potent inhibitor (IC50 value = 0.6 microM) of rat 17 alpha-hydroxylase/17,20-lyase.
Njar
V C
VC
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
Klus
G T
GT
Johnson
H H
HH
Brodie
A M
AM
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D011278:Pregnanes / Q000737:chemistry*; D011283:Pregnenes / Q000737:chemistry*; D051381:Rats; D017550:Spectroscopy, Fourier Transform Infrared; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
C107426:20-hydroxy-21,21,21,-trifluoropregn-4-en-3-one; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011278:Pregnanes; D011283:Pregnenes; D013254:Steroid 17-alpha-Hydroxylase