Squalene analogues containing isopropylidene mimics as potential inhibitors of pig liver squalene epoxidase and oxidosqualene cyclase.
Several squalene analogues containing 1,1-dihaloalkene, acetylene, allene, diene, and cyclopropane functionalities were synthesized and evaluated as potential inhibitors of pig liver squalene epoxidase and oxidosqualene cyclase. Both monofunctionalized and bisfunctionalized analogues were prepared. Poor inhibition of squalene epoxidase and oxidosqualene cyclase was found for most compounds (IC50 much greater than 400 microM), with the exception of the monofunctionalized alkynol (IC50 = 300 microM). This alkynol showed mixed-function inhibition with KI = 0.95 mM. Oxidation of the alcohol to the alkynone resulted in loss of epoxidase activity, indicating that the hydroxyl group is necessary for inhibition and that the alkynol is not a proinhibitor. Molecular mechanics calculations indicated that a good inhibitor should possess hydrophobic substituents on an unpolarized, unsaturated system; additionally, the presence of a pro-C-3 hydroxyl group can confer inhibitory potency.
Department of Chemistry, State University of New York, Stony Brook 11794-3400.
S E
SE
Sen
G D
GD
Prestwich
D000475:Alkenes / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D013185:Squalene / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D050603:Squalene Monooxygenase; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D000475:Alkenes; D013185:Squalene; D010105:Oxygenases; D050603:Squalene Monooxygenase; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase