- 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
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A series of cinnamic acid derivatives were prepared and their biological activities were evaluated in lipoprotein metabolism. 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) showed potent anti-atherogenic and anti-oxidant activities. 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 IC50 around 60 and 95 μM, 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 μM, compound 1 and 2, respectively. Additionally, decrease of HDL-particle size under presence of LDL was inhibited by the 1 at 307 μM 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,Han, Jong-Min,Kim, Hyunjung,Kim, Eungsoo,Jeong, Tae-Sook,Lee, Woo Song,Cho, Kyung-Hyun
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- Structure-activity relationship of clovamide and its related compounds for the inhibition of amyloid β aggregation
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Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of amyloid β-protein (Aβ). Aβ aggregates through β-sheet formation and induces cytotoxicity against neuronal cells. Inhibition of Aβ aggregation by naturally occurring compounds is thus a promising strategy for the treatment of AD. We have already reported that caffeoylquinic acids and phenylethanoid glycosides, which possess two or more catechol moieties, strongly inhibited Aβ aggregation. Clovamide (1) containing two catechol moieties, isolated from cacao beans (Theobroma cacao L.), is believed to exhibit preventive effects on Aβ aggregation. To investigate the structure-activity relationship of clovamide (1) for the inhibition of Aβ aggregation, we synthesized 1 and related compounds 2–11 through reaction between L-DOPA, D-DOPA, L-tyrosine, or L-phenylalanine and caffeic acid, p-coumaric acid, or cinnamic acid, and compounds 12 and 13 were derived from 1. Among tested compounds 1–13, those containing one or two catechol moieties exhibited potent anti-aggregation activity, whereas the non-catechol-type related compounds showed little or no activity. This suggests that at least one catechol moiety is essential for inhibition of Aβ42 aggregation, and this activity increases depending on the number of catechol moieties. Consequently, clovamide (1) and its related compounds may be a promising therapeutic option for inhibiting Aβ-mediated pathology in AD.
- Tsunoda, Tatsuhiko,Takase, Mio,Shigemori, Hideyuki
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p. 3202 - 3209
(2018/05/05)
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