Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase

Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C-2-C-18) esters of hexahydroxydiphenyl (HHDP) dicarboxylic acid were evaluated as enzyme inhibitors of recombinant rat squalene epoxidase, a rate-limiting enzyme of cholesterol biosynthesis. Among the ellagitannins tested, pedunculagin (IC50 = 2.0 muM) and eugeniin (IC50 = 1.6 muM), both containing (S)-HHDP ester group(s), showed remarkable inhibition, which was more potent than those of previously reported substrate analogue inhibitors. Furthermore, ellagic acid IC50 = 2.0 muM), a bislactone formed by hydrolytic release of a HHDP group from ellagitannins, was also a good inhibitor of the enzyme. On the other hand, the synthetic IMP esters with C-6 (IC50 = 0.93 muM) and C-8 alkyl side chains (IC50 = 0.83 muM) showed potent enzyme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C-1-C-4) and a Cis ester exhibited moderate inhibition (IC50 = 8-47 muM).