Ellagitannins and Hexahydroxydiphenoyl Esters as Inhibitors of Vertebrate Squalene Epoxidase

Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C1−C18) 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 μM) and eugeniin (IC50 = 1.6 μM), 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 μM), 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 HHDP esters with C6 (IC50 = 0.93 μM) and C8 alkyl side chains (IC50 = 0.83 μM) showed potent enzyme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C1−C4) and a C18 ester exhibited moderate inhibition (IC50 = 8−47 μM).