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 corresp onding N-oxide, 22,23-epoxy-2-aza-2,3-dihydrosqualene-N-oxide, to inhi bit sterol biosynthesis were studied in microsomes and cells of Saccha romyces cerevisiae and Candida albicans. 22,23-Epoxy-2-aza-2,3-dihydro squalene, which differs from the other inhibitor only in lacking oxyge n at position 2, exhibited higher inhibitory properties in all prepara tions tested. The different levels of effectiveness of the two azasqua lene derivatives were evident mostly in microsomes from S. cerevisiae (the 50 inhibitory concentrations of the 2-aza derivative and the corr esponding N-oxide on oxidosqualene cyclase were 30 and 120 mu M respec tively) and in cell cultures of the same strain (1 order of magnitude separated the inhibitory activities of the two compounds on sterol bio synthesis). A possible explanation for the differences between 22,23-e poxy-2-aza-2,3-dihydrosqualene and the corresponding N-oxide arose fro m the study of their metabolic fates in vivo and in vitro. While the 2 -aza derivative did not undergo any transformation, the N-oxide compou nd was actively reduced to the corresponding amine in microsomes and i n cells of both yeast strains. 22,23-Epoxy-2-aza-2,3-dihydrosqualene-N -oxide seems to behave as a proinhibitor of sterol biosynthesis, becom ing active only after transformation into the active form 22,23-epoxy- 2-aza-2,3-dihydrosqualene.