Caffeoyl and cinnamoylclusters with anti-inflammatory and anti-cancer effects. Synthesis and structure–activity relationship

Abstract

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 IC₅₀ values ranging from 0.66 to 0.79 μM. 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.