Inhibition of sterol biosynthesis in Saccharomyces cerevisiae and Candida albicans by 22,23-epoxy-2-aza-2,3-dihydrosqualene and the corresponding N-oxide.
The abilities of 22,23-epoxy-2-aza-2,3-dihydrosqualene and the corresponding N-oxide, 22,23-epoxy-2-aza-2,3-dihydrosqualene-N-oxide, to inhibit sterol biosynthesis were studied in microsomes and cells of Saccharomyces cerevisiae and Candida albicans. 22,23-Epoxy-2-aza-2,3-dihydrosqualene, which differs from the other inhibitor only in lacking oxygen at position 2, exhibited higher inhibitory properties in all preparations tested. The different levels of effectiveness of the two azasqualene derivatives were evident mostly in microsomes from S. cerevisiae (the 50 inhibitory concentrations of the 2-aza derivative and the corresponding N-oxide on oxidosqualene cyclase were 30 and 120 microM respectively) and in cell cultures of the same strain (1 order of magnitude separated the inhibitory activities of the two compounds on sterol biosynthesis). A possible explanation for the differences between 22,23-epoxy-2-aza-2,3-dihydrosqualene and the corresponding N-oxide arose from the study of their metabolic fates in vivo and in vitro. While the 2-aza derivative did not undergo any transformation, the N-oxide compound was actively reduced to the corresponding amine in microsomes and in cells of both yeast strains. 22,23-Epoxy-2-aza-2,3-dihydrosqualene-N-oxide seems to behave as a proinhibitor of sterol biosynthesis, becoming active only after transformation into the active form 22,23-epoxy-2-aza-2,3-dihydrosqualene.
Balliano
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Istituto di Chimica Farmaceutica Applicata, Torino, Italy.
Milla
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P
Ceruti
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M
Carrano
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L
Viola
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F
Brusa
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P
Cattel
L
L
D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D013185:Squalene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013261:Sterols / Q000096:biosynthesis*
D004852:Epoxy Compounds; D005656:Fungal Proteins; D013261:Sterols; C067257:22,23-epoxy-2-aza-2,3-dihydrosqualene; C067258:22,23-epoxy-2-aza-2,3-dihydrosqualene N-oxide; D013185:Squalene; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase