Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase

Abe, I Kashiwagi, Y Noguchi, H Tanaka, T Ikeshiro, Y Kashiwada, Y

I. Abe et al., Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase, J NAT PROD, 64(8), 2001, pp. 1010-1014

28

INGLESE

Article

Agricultural Chemistry","Pharmacology & Toxicology

JOURNAL OF NATURAL PRODUCTS

0163-3864 → ACNP

64

8

2001

1010 - 1014

ISI

0163-3864(200108)64:8<1010:EAHEAI>2.0.ZU;2-P

Ellagitannins isolated from various plant sources as well as newly synthesi zed n-alkyl (C-2-C-18) esters of hexahydroxydiphenyl (HHDP) dicarboxylic ac id were evaluated as enzyme inhibitors of recombinant rat squalene epoxidas e, a rate-limiting enzyme of cholesterol biosynthesis. Among the ellagitann ins tested, pedunculagin (IC50 = 2.0 muM) and eugeniin (IC50 = 1.6 muM), bo th containing (S)-HHDP ester group(s), showed remarkable inhibition, which was more potent than those of previously reported substrate analogue inhibi tors. Furthermore, ellagic acid IC50 = 2.0 muM), a bislactone formed by hyd rolytic release of a HHDP group from ellagitannins, was also a good inhibit or of the enzyme. On the other hand, the synthetic IMP esters with C-6 (IC5 0 = 0.93 muM) and C-8 alkyl side chains (IC50 = 0.83 muM) showed potent enz yme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C-1-C-4) and a Cis ester exhibited moderate inhibiti on (IC50 = 8-47 muM).