Squalene analogues containing isopropylidene mimics as potential inhibitors of pig liver squalene epoxidase and oxidosqualene cyclase.

摘要: Several squalene analogues containing 1,1-dihaloalkene, acetylene, allene, diene, and cyclopropane functionalities were synthesized evaluated as potential inhibitors of pig liver epoxidase oxidosqualene cyclase. Both monofunctionalized bisfunctionalized prepared. Poor inhibition cyclase was found for most compounds (IC50 much greater than 400 microM), with the exception alkynol = 300 microM). This showed mixed-function KI 0.95 mM. Oxidation alcohol to alkynone resulted in loss activity, indicating that hydroxyl group is necessary not a proinhibitor. Molecular mechanics calculations indicated good inhibitor should possess hydrophobic substituents on an unpolarized, unsaturated system; additionally, presence pro-C-3 can confer inhibitory potency.