Synthesis of sulfur- and sulfoxide-substituted 2,3-oxidosqualenes and their evaluation as inhibitors of 2,3-oxidosqualene-lanosterol cyclase

Article abstract of DOI:10.1021/ja00107a011

2,3-Oxidosqualene (23-OS) analogs that contain thioether (52-55) and sulfoxide (56-60) at positions normally occupied by carbons considered to be cationic during 2,3-oxidosqualene-lanosterol cyclase (OSC) cyclization (C-6, C-10, C-14, and C-19) were synthesized and tested as substrate mimic inhibitors of fungal and mammalian OSC. The analogs were found to be potent inhibitors of cyclase in cell-free extracts of Candida albicans and rat liver. Thioether analogs were more potent than the corresponding sulfoxides. In both series, those 2,3-OS analogs containing 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 μM while 60 exhibited an IC₅₀ of 0.065 μM, which are the lowest values reported for a inhibitor of this enzyme. Similarly, thioether 55 displayed an IC₅₀ of 0.00082 μM 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 affinity for the active site of these enzymes. The same series of analogs (52-60) were also tested for inhibition of cholesterol biosynthesis in intact MDBK (Madin Darbin bovine kidney) cells and for in vitro antifungal activity against C. albicans.