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Synthesis of vinyl sulfide analogs of 2,3-oxidosqualene and their inhibition of 2,3-oxidosqualene lanosterol-cyclases

Authors
Journal
Tetrahedron
0040-4020
Publisher
Elsevier
Publication Date
Volume
51
Issue
18
Identifiers
DOI: 10.1016/0040-4020(95)00213-r
Disciplines
  • Mathematics

Abstract

Abstract Syntheses of all trans (6 E)-5-, (10 E)-9-, (14 E)-16- and (18 E)-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 separated by chromatography and the syn isomers were transformed to the E-vinyl sulfides. Both (6 E)-5- and (18 E)-20-thia-2,3-OS inhibited OSC from Candida albicans (IC 50 = 47 and 0.2 μM, respectively) and rat liver (IC 50 = 7.7 and 0.32 μM, respectively). Their activities were compared with those of previously synthesized (6 E)-8- and (14 E)-13-thia-2,3-OSs (IC 50 = 0.68 and 45 μM, C. albicans, IC 50 = 34 and 61 μM, rat liver, respectively). The best inhibitor among these compounds for the OSC of C. albicans and rat liver is the (18 E)-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.

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