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

Article abstract of DOI:10.1021/jm00094a020

2,3-Epoxy-10-aza-10,11-dihydrosqualene, a high-energy intermediate analogue inhibitor of 2,3-xidosqualene (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 μM.Both E and Z isomers were inactive on squalene epoxidase at the higher concentrations tested.