Novel Aromatic Ester fromPiper longumand Its Analogues Inhibit Expression of Cell Adhesion Molecules on Endothelial Cells

Abstract

We report here the isolation and characterization of two active principles, ethyl 3',4',5'-trimethoxycinnamate (1) and piperine (2), from the combined hexane and chloroform extracts of Piper longum. Using primary human umbilical vein endothelial cells, we evaluated the activities of compound 1 on TNF-alpha-induced expression of cell adhesion molecules, viz., ICAM-1, VCAM-1, and E-selectin, which play key roles in controlling various inflammatory diseases. Both compounds 1 and 2 inhibited the TNF-alpha-induced expression of ICAM-1 in a dose- and time-dependent manner; however, the activity of ethyl 3',4',5'-trimethoxycinnamate (1) was approximately 1.3 times higher than that of piperine (2). As ethyl 3',4',5'-trimethoxycinnamate (1) has been isolated for the first time from a natural source, Piper longum, and it exhibited higher activity, we carried out further studies on it. To correlate its cell adhesion molecule inhibitory activity with its functional consequences, we showed that it significantly blocked the adhesion of neutrophils to endothelium in a time- and concentration-dependent manner. Importantly, the inhibitory effect of cinnamate 1 was found to be reversible. To elucidate its structure-function-activity relationship, we synthesized nine different analogues of ethyl 3',4',5'-trimethoxycinnamate, i.e., compounds 3-11, and compared the ICAM-1 inhibitory activity of compound 1 with those of its synthetic analogues as well as the corresponding acids 12-15. The structure-activity studies indicate that the chain length of the alcohol moiety, substituents in the aromatic ring, and alpha, beta-double bond of the cinnamic acid ester have significant effects on the inhibition of TNF-alpha-induced expression of ICAM-1 on endothelial cells. These findings have implications in developing compounds with a better therapeutic index against various inflammatory diseases.

Ethyl Cinnamate Derivatives as Promising High-Efficient Acaricides against <i>Psoroptes cuniculi</i>: Synthesis, Bioactivity and Structure–Activity Relationship

“…Unlike the situation of nitro group, the introduction of a hydroxyl, methoxyl or acetoxyl to any site on the benzene ring (7-15) led to reduce the activity. Meanwhile, the activities of methoxyl-substituted compounds (18)(19)(20) reduced with increasing the number of substituted methoxy groups. In addition, the presence of methylenedioxy, bromo or chloro groups at some sites also led to reduction of the activity, such as 21-25.…”

“…10) Due to their common occurrence in plants and their low toxicity, 11,12) cinnamic acid derivatives have attracted much attention of many pharmacologists. In the past decades, cinnamic acid derivatives including natural, semi-synthetic and synthetic compounds had been proven to have a variety of pharmacological activities, 13) such as anticancer, 14,15) antimicrobial, [16][17][18] antioxidative, 18) anti-inflammatory, 15,[19][20][21] anti-Mycobactrium tuberculosis, [22][23][24] antiviral, 25) anti-human immunodeficiency virus (HIV), [26][27][28] antidiabetic, 29) anticholesterolemic, 30) analgesic, 31) hepatoprotective, 32,33) immunoprotective, 34) inducing neural progenitor cell proliferation 35) and anxiolytic activity. 36) Especially, what interests us is that cinnamic acid derivatives also have significant antiparasitic activities on plasmodia, 37) Leishmania 38) and nematode.…”

Effect of Caffeic Acid on Tumor Necrosis Factor-Alpha-Induced Vascular Inflammation in Human Umbilical Vein Endothelial Cells

“…35,36) The efficacy of several identified compounds have also been tested using in vivo models. [37][38][39] Inhibition of these molecules by various small molecules has been shown to downregulate the expression of cell adhesion molecules and is effective in controlling various inflammatory diseases. 40) This study, confirmed that TNF-a induced NF-kB-DNA complex formation was attenuated in the presence of CA.…”

Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids

“…Primary endothelial cells were isolated from human umbilical cord using mild trypsinization as described earlier 36 .…”

“…A promising approach for the therapeutic intervention of inflammatory disorders is by pharmacological inhibition of the CAM expression of endothelial cells 33 . In order to develop safer and potent anti-inflammatory agents/drugs, our laboratories have identified a number of small molecules from natural/synthetic sources that efficiently block nuclear accumulation of NF-kB and abrogate TNF-a-induced expression of E-selectin, VCAM-1 and ICAM-1 on human umbilical vein endothelial cells (HUVEC's) [34][35][36] .…”