Novel aromatic ester from Piper longum and its analogues inhibit expression of cell adhesion molecules on endothelial cells.
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.
Kumar
Sarvesh
S
Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110 007, India.
Arya
Pragya
P
Mukherjee
Chandrani
C
Singh
Brajendra K
BK
Singh
Naresh
N
Parmar
Virinder S
VS
Prasad
Ashok K
AK
Ghosh
Balaram
B
D000470:Alkaloids / Q000494:pharmacology; D052117:Benzodioxoles; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology*; D019040:E-Selectin / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D031701:Piper / Q000737:chemistry*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D000470:Alkaloids; D052117:Benzodioxoles; D015815:Cell Adhesion Molecules; D002934:Cinnamates; D019040:E-Selectin; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C507419:ethyl 3',4',5'-trimethoxycinnamate; D018799:Intercellular Adhesion Molecule-1; C008922:piperine