Synthesis of Vinyl Sulfide Analogs of 2,3-Oxidosqualene and Their Inhibition of 2,3-Oxidosqualene Lanosterol-Cyclases

Article abstract of DOI:10.1016/0040-4020(95)00213-R

Syntheses of all trans(6E)-5-, (10E)-9-, (14E)-16- and (18E)-20-thia-2,3-oxidosqualenes as inhibitors of 2,3-oxidosqualene-lanosterol cyclase (OSC) are reported.To mimic the natural geometry of 2,3-oxidosqualene (2,3-OS), we required E-vinyl sulfides which were prepared by condensation of sulfur-substituted Wittig-Horner reagents (α-thioterpenoidyl diphenylphosphine oxides) with appropriate aldehydes.Mixtures of syn and anti α-hydroxydiphenylphosphine adducts were seperated by chromatography and the syn isomers were transformed to the E-vinyl sulfides.Both (6E)-5- and (18E)-20-thia-2,3-OS inhibited OSC from Candida albicans (IC50 = 47 and 0.2 μM, respectively) and rat liver (IC50 = 7.7 and 0.32 μM, respectively).Their activities were compared with those of previously synthesized (6E)-8- and (14E)-13-thia-2,3-Oss (IC50 = 0.68 and 45 μM, C. albicans, IC50 = 34 and 61 μM, rat liver, respectively).The best inhibitor among these compounds for the OSC of C. albicans and rat liver is the (18E)-20-thia-2,3-OS.This result suggests that modification of C-20 region of the 2,3-OS skeleton is an attractive strategy for development of OSC inhibitors.