Synthesis of cinnamic acid derivatives and their inhibitory effects on LDL-oxidation, acyl-CoA:cholesterol acyltransferase-1 and -2 activity, and decrease of HDL-particle size.
A series of cinnamic acid derivatives were synthesized and their biological abilities on lipoprotein metabolism were examined. Among the tested compounds, 4-hydroxycinnamic acid (l-phenylalanine methyl ester) amide (1) and 3,4-dihydroxyhydrocinammic acid (l-aspartic acid dibenzyl ester) amide (2) inhibited human acyl-CoA:cholesterol acyltransferase-1 and -2 activities with apparent IC(50) around 60 and 95 microM, respectively. Compounds 1 and 2 also served as an antioxidant against copper mediated low-density lipoproteins (LDL) oxidation with apparent IC(50)=52 and 3 microM, compound 1 and 2, respectively. Additionally, decrease of HDL-particle size under presence of LDL was inhibited by the 1 at 307 microM of final concentration. Treatment of the 1 or 2 did not influence normal growth of RAW264.7 without detectable cytotoxic activity from a cell viability test. These results suggest that the new cinnamic acid derivatives possess useful biological activity as an anti-atherosclerotic agent with inhibition of cellular cholesterol storage and transport by the both ACAT, inhibition of LDL-oxidation, HDL particle size rearrangement.
Lee
Sangku
S
National Research Laboratory of Lipid Metabolism and Atherosclerosis, Korea Research Institute of Bioscience and Biotechnology, 52 Eoun-dong, Yuseong-gu, Daejeon 305-333, South Korea.
Han
Jong-Min
JM
Kim
Hyunjung
H
Kim
Eungsoo
E
Jeong
Tae-Sook
TS
Lee
Woo Song
WS
Cho
Kyung-Hyun
KH
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D004587:Electrophoresis, Agar Gel; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors; D000097587:Sterol O-Acyltransferase 2
D000409:Alanine; D000975:Antioxidants; D001224:Aspartic Acid; D002934:Cinnamates; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010649:Phenylalanine; D002785:Sterol O-Acyltransferase; D017392:Thiobarbituric Acid Reactive Substances; D000097587:Sterol O-Acyltransferase 2; C497005:3,4-dihydroxyhydrocinammic acid (L-alanine methyl ester) amide; C497003:3,4-dihydroxyhydrocinammic acid (l-aspartic acid dibenzyl ester) amide; C497004:4-hydroxycinnamic acid (l-phenylalanine methyl ester) amide; C493492:sterol O-acyltransferase 1