The caffeic acid scaffold, which is abundant in nature, is extremely versatile and is found in a number of biologically active molecules. The purpose of this review is to provide an overview of the pharmacological activity of synthetic caffeic acid analogs including recent reports of anti-inflammatory, anti-cancer, and antiviral activities of these compounds.
Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β-unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5-LO in a concentration-dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC of 0.3 μm, SAPE (10) was threefold more potent than CAPE (2) and 10-fold more potent than zileuton (1), the only 5-LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12-lipoxygenase (12-LO) and less effect on cyclooxygenase 1 (COX-1) which makes it a more selective 5-LO inhibitor.
The syntheses of twelve caffeoyl/cinnamoyl clusters and their anti-inflammatory and anti-cancer effects are described. Synthesis of the title compounds involved a multiple copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Azide or alkyne functionalized cinnamoyl or caffeoyl moieties are attached to the selected core molecules to allow variation of the introduced cinnamoyl or caffeoyl moieties in order to compare their effects on 5-lipoxygenase (5-LO) inhibition and on cell proliferation in cancerous (MCF7) and non cancerous (MCF10A) human mammary epithelial cell lines. Caffeoyl dimer 13, trimer 17, and tetramer 19, inhibited 5-LO product synthesis in a cell-free assay with IC 50 values ranging from 0.66 to 0.79 mM. These compounds surpassed the inhibitory activity of caffeic acid by more than 10-fold. Monomer 11 caused almost 95% inhibition of 5-LO and surpassed the known 5-LO inhibitor zileuton in a cell-based assay. Trimer compounds 15, 17 and tetramer 19 decreased proliferation rates of MCF-7 cells by 36, 23 and 47%, respectively, but had no effect on MCF10A proliferation.
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