Synthesis and bioevaluation of delta 7-5-desaturase inhibitors, an enzyme late in the biosynthesis of the fungal sterol ergosterol.
Ergosterol, 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.
Goldstein
A S
AS
Cogswell Lab, Renessalear Polytechnic Institute, Troy, New York 12180, USA.
Frye
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LL
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004875:Ergosterol / Q000096:biosynthesis*; D005658:Fungi / Q000201:enzymology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D013055:Spectrophotometry, Infrared
D004791:Enzyme Inhibitors; C033144:lathosterol delta-5-dehydrogenase; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D004875:Ergosterol