Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 13, Issue 5, Pages 1867-1872Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2004.10.065
Keywords
corynoline; alkaloid; cell adhesion inhibitory activity; structure-activity relationship
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Corynoline (1), a hexahydrobenzo[c]phenanthridine-type alkaloid, exhibited the concentration-dependent inhibition for the adhesion of human polymorphonuclear leukocyte and eosinophil to human umbilical vein cultured endothelial cell in the concentration range of showing no significant cytotoxicity for the cell: IC50 value = 72.4 muM for (d)-1 and 156.7 muM for (1)-1. This shows the potent anti-inflammatory and/or immunosuppressive activity of 1. To elucidate possible structure-activity relationship, the conformational/structural feature of (d)-1 was investigated by X-ray crystal structure analysis and molecular orbital energy calculations, and the docking study was performed for its interaction with the D1-domain of ICAM-1 (intracellular adhesion molecule-]). A plausible model was proposed, in which all polar atoms of (d)-1 are linked by hydrogen bonds or electrostatic interactions with the functional residues of ICAM-1, that have been supposed to be necessary for the binding with LFA-1 (leukocyte function-associated antigen-1). This suggests the potent inhibitory activity of 1 for the ICAM-1/LFA-1 adhesion and would be important on developing the clinically usable drugs for the inflammatory diseases. (C) 2004 Elsevier Ltd. All rights reserved.
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