Potent and Selective Inhibition of Squalene Epoxidase by Synthetic Galloyl Esters

Abstract

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 μM) showed the most potent inhibition, which was far more potent than those of previously reported naturally occurring gallocatechins. Octyl gallate (5) (IC50 = 0.83 μM) and cetyl gallate (7) (IC50 = 0.59 μM) also showed good inhibition, while gallic acid (IC50 = 73 μM) itself was not so active. In addition, chemically synthesized galloyl ester of cholesterol (9) (IC50 = 3.9 μM), farnesol derivative (10) (IC50 = 0.57 μM), and dodecyl galloyl amide (8) (IC50 = 3.0 μM) were also potent inhibitors of SE. Inhibition kinetics revealed that dodecyl gallate inhibited SE in competitive (KI = 0.033 μM) 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.