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International Journal of Medicinal Chemistry
Volume 2014, Article ID 931756, 12 pages
http://dx.doi.org/10.1155/2014/931756
Research Article

Clicked Cinnamic/Caffeic Esters and Amides as Radical Scavengers and 5-Lipoxygenase Inhibitors

1Département de Chimie et Biochimie, Université de Moncton, Moncton, NB, Canada E1A 3E9
2Centre de Recherche en Rhumatologie et Immunologie et Faculté de Médecine, Université Laval, Québec, QC, Canada G1V 4G2

Received 13 September 2013; Revised 12 December 2013; Accepted 13 December 2013; Published 18 February 2014

Academic Editor: Patrick Bednarski

Copyright © 2014 Jérémie A. Doiron et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

5-Lipoxygenase (5-LO) is the key enzyme responsible for the conversion of arachidonic acid to leukotrienes, a class of lipid mediators implicated in inflammatory disorders. In this paper, we describe the design, synthesis, and preliminary activity studies of novel clicked caffeic esters and amides as radical scavengers and 5-LO inhibitors. From known 5-LO inhibitor 3 as a lead, cinnamic esters 8a–h and amides 9a–h as well as caffeic esters 15a–h and amides 16a–h were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloaddition with the appropriate azide precursors and terminal alkynes. All caffeic analogs are proved to be good radical scavengers (IC50: 10–20 μM). Esters 15g and 15f possessed excellent 5-LO inhibition activity in HEK293 cells and were equipotent with the known 5-LO inhibitor CAPE and more potent than Zileuton. Several synthesized esters possess activities rivaling Zileuton in stimulated human polymorphonuclear leukocytes.