Potent and selective inhibition of squalene epoxidase by synthetic galloyl esters

n-Alkyl esters (ethyl, octyl, dodecyl, and cetyl) of gallic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase (SE), a rate-limiting enzyme of cholesterol biogenesis. Dodecyl (6) (IC50 = 0.061 mu M) showed the most potent inhibition, which was far more potent than those of previously reported naturally occurring: gallocatechins. Octyl gallate (5) (IC50 = 0.83 mu M) and cetyl gallate (7) (IC50 = 0.59 mu M) also showed good inhibition, while gallic acid (IC50 = 73 mu M) itself was not so active. In addition, chemically synthesized galloyl ester of cholesterol (9) (IC50 = 3.9 mu M), farnesol derivative (10) (IC50 = 0.57 mu M) and dodecyl galloyl amide (8) (IC50 = 3.0 mu M) were also potent inhibitors of SE. Inhibition kinetics revealed that dodecyl gallate inhibited SE in competitive (K-I = 0.033 mu M) and no-time-dependent manner. The potent inhibition of the flavin monooxygenase would be caused by specific binding to the enzyme, and by scavenging reactive oxygen species required for the epoxidation reaction. (C) 2000 Academic Press.