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-dihydroxyhydro-cinammic acid (L-aspartic acid dibenzyl ester) amide (2) inhibited human acyl-CoA:cholesterol acyltransferase-1 and -2 activities with apparent IC50 around 60 and 95 muM, respectively. Compounds 1 and 2 also served as an antioxidant against copper mediated low-density lipoproteins (LDL) oxidation with apparent IC50 = 52 and 3 muM, compound 1 and 2, respectively. Additionally, decrease of HDL-particle size under presence of LDL was inhibited by the 1 at 307 muM 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. (C) 2004 Elsevier Ltd. All rights reserved.