Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis.
The synthesis of some novel azasteroids and thiasteroids based on a pregnan nucleus with a Delta7 double bond in two to five steps from the key aldehyde (3S,20S)-20-formylpregn-7-en-3-yl acetate has been disclosed herein. These compounds were evaluated as potential inhibitors of the enzyme Delta24-sterol methyltransferase (24-SMT), which is a key enzyme in the biosynthesis of ergosterol, and for their effects on the growth of the yeast Yarrowia lipolytica. Most of the side chain modified analogues were recognized as 24-SMT inhibitors, and in particular the 23-azasteroids 5f-5i and the 24-azasteroid 11 showed potent antifungal activity. The target enzyme could be identified unambiguously using an improved whole-cell assay combined with GC-MS analysis of the sterol pattern resulting upon incubation with the inhibitors.
Renard
Delphine
D
Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 Munich, Germany.
Perruchon
Johann
J
Giera
Martin
M
Müller
Jörg
J
Bracher
Franz
F
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001378:Azasteroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004875:Ergosterol / Q000096:biosynthesis*; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D025062:Yarrowia / Q000254:growth & development
D000935:Antifungal Agents; D001378:Azasteroids; D004791:Enzyme Inhibitors; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase; D004875:Ergosterol