2,3-Epoxy-10-aza-10,11-dihydrosqualene, a High-Energy Intermediate Analogue Inhibitor of 2,3-oxidosqualene Cyclase

J Med Chem. 1992 Aug 7;35(16):3050-8. doi: 10.1021/jm00094a020.

Abstract

2,3-Epoxy-10-aza-10,11-dihydrosqualene, a high-energy intermediate analogue inhibitor of 2,3-oxidosqualene (SO) cyclase was obtained by total synthesis. This involved the preparation of three main building blocks: (1) C17 squalenoid N-methylamine, (2) 3-(diphenylphosphinoyl)propanal, and (3) 5,6-epoxy-6-methylheptan-2-one. The final stages of the reconstruction of the 6E double bond were obtained by a Wittig-Horner reaction which was modified for poorly reactive systems. This compound was designed to mimic the C-8 carbonium ion formed during SO cyclization. Its inhibitory activity on various SO cyclases was evaluated and compared with the 6 Z isomer which has an unfavorable geometry. Only isomer 6 E, the carbocation analogue, was active on SO cyclases from rat liver, pig liver, S. cerevisiae, and C. albicans microsomes, with an I50 varying from 3 to 5 microM. Both E and Z isomers were inactive on squalene epoxidase at the higher concentrations tested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Candida albicans / enzymology
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology*
  • Intramolecular Transferases*
  • Isomerases / antagonists & inhibitors*
  • Magnetic Resonance Spectroscopy
  • Microsomes, Liver / enzymology
  • Rats
  • Saccharomyces cerevisiae / enzymology
  • Squalene / analogs & derivatives*
  • Squalene / chemistry
  • Squalene / pharmacology
  • Swine

Substances

  • Epoxy Compounds
  • 2,3-epoxy-10-aza-10,11-dihydrosqualene
  • Squalene
  • Isomerases
  • Intramolecular Transferases
  • lanosterol synthase