Synthesis and Bioevaluation of Δ 7 -5-Desaturase Inhibitors, an Enzyme Late in the Biosynthesis of the Fungal Sterol Ergosterol
1996; American Chemical Society; Volume: 39; Issue: 26 Linguagem: Inglês
10.1021/jm9605851
ISSN1520-4804
Autores Tópico(s)Microbial Natural Products and Biosynthesis
ResumoErgosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolutely necessary for growth. The delta 5-double bond appears to be required for the regulatory role of ergosterol; therefore, development of inhibitors of the enzyme that introduce this double bond, delta 7-sterol 5-desaturase (5-desaturase), may lead to effective antifungal agents. Within is the first reported synthesis of inhibitors of fungal 5-desaturase and the development of an in vitro tritium efficacy radioassay. The inhibitors were of the general structure 7,22(E)-ergostadien-3 beta-ol with alpha-face heteroatom substituents in the vicinity of C-5. They exhibited IC50 values of 47-149 microM.
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