SULFUR-SUBSTITUTED AND SULFOXIDE-SUBSTITUTED 2,3-OXIDOSQUALENES AND THEIR EVALUATION AS INHIBITORS OF 2,3-OXIDOSQUALENE-LANOSTEROL CYCLASE

2,3-Oxidosqualene (23-OS) analogs that contain thioether (52-55) and s ulfoxide (56-60) at positions normally occupied by carbons considered to be cationic during 2,3-oxidosqualene-lanosterol cyclase (OSC) cycli zation (C-6, C-10, C-14, and C-19) were synthesized and tested as subs trate mimic inhibitors of fungal and mammalian OSC. The analogs were f ound to be potent inhibitors of cyclase in cell-free extracts of Candi da albicans and rat liver. Thioether analogs were more potent than the corresponding sulfoxides. In both series, those 2,3-OS analogs contai ning a sulfur at the position normally occupied by C-19 were the most potent. With C. albicans cyclase, the IC50 for thioether 55 was 0.0023 mu M while 60 exhibited an IC50 of 0.065 mu M, which are the lowest v alues reported for a inhibitor of this enzyme. Similarly, thioether 55 displayed an IC50 of 0.00082 mu M for rat liver cyclase which is the best inhibitor up to date for this enzyme. These results suggest that mimics with modification in the region of C-19 of 2,3-OS have a high a ffinity for the active site of these enzymes. The same series of analo gs (52-60) were also tested for inhibition of cholesterol biosynthesis in intact MDBK (Madin Darbin bovine kidney) cells and for in vitro an tifungal activity against C. albicans.