Side chain azasteroids and thiasteroids as sterol methyltransferase inhibitors in ergosterol biosynthesis |
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Authors: | Delphine Renard Johann Perruchon Martin Giera Jörg Müller Franz Bracher |
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Institution: | Department Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität, Butenandtstraße 5-13, 81377 Munich, Germany |
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Abstract: | The synthesis of some novel azasteroids and thiasteroids based on a pregnan nucleus with a Δ7 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 Δ24-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. |
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