Ellagitannins and hexahydroxydiphenoyl esters as inhibitors of vertebrate squalene epoxidase.
Ellagitannins isolated from various plant sources as well as newly synthesized n-alkyl (C(1)-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 (IC(50) = 2.0 microM) and eugeniin (IC(50) = 1.6 microM), 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 (IC(50) = 2.0 microM), 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 C(6) (IC(50) = 0.93 microM) and C(8) alkyl side chains (IC(50) = 0.83 microM) showed potent enzyme inhibition at the submicromolar concentration range, while esters with shorter chain lengths (C(1)-C(4)) and a C(18) ester exhibited moderate inhibition (IC(50) = 8-47 microM).
Abe
I
I
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. abei@ys7.u-shizuoka-ken.ac.jp
Kashiwagi
Y
Y
Noguchi
H
H
Tanaka
T
T
Ikeshiro
Y
Y
Kashiwada
Y
Y
D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004952:Esters / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047348:Hydrolyzable Tannins; D015394:Molecular Structure; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013185:Squalene / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013634:Tannins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D004952:Esters; D047348:Hydrolyzable Tannins; D011994:Recombinant Proteins; D013634:Tannins; C013515:ellagitannin; D013185:Squalene; D013186:Farnesyl-Diphosphate Farnesyltransferase