Caffeoyl and cinnamoyl clusters 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 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.

Antioxidative Activities of Natural Hydroxy-Bearing Cinnamaldehydes and Cinnamic Acids: A Comparative Study

“…Hydroxy-bearing cinnamic acids are naturally abundant antioxidants in our diet, such as pcoumaric acid, and caffeic acid, which have a variety of biological activities, such as anticancer [3], antimutation [4], and antioxidation [5], hepatoprotective etc [6,7]. Some hydroxybearing cinnamaldehydes, such as ocoumaraldehyde from bark of cinnamon，p-coumaraldehyde， ferulaldehyde，and caffeic aldehyde have been widely studied and found to be good bioactive compounds.…”

Structure–activity relationship of caffeic acid phenethyl ester analogs as new 5‐lipoxygenase inhibitors

“…Furthermore, assays of multivalent compounds showed that inhibitory activity of caffeates is not proportional to the number of caffeoyl groups present in a compound . Although most of the caffeoyl esters synthesized in these studies had excellent and similar 5‐LO inhibition potential in HEK293 cell lysates, large variability in inhibition was found when performing assays on whole cells . Such differences in activity among structurally similar compounds possessing identical pharmacophores may indicate the important influence of structure and steric bulk on cell permeability and hydrophobic interactions.…”

“…However, antioxidant activity is not sufficient to assure efficient 5‐LO inhibition in complex systems: caffeic acid ( 2 ) and the amide analog of CAPE ( 3 ), which are roughly equipotent with CAPE ( 3 ) in radical scavenging assays, possess far lower inhibitory activity in PMNL and whole blood assays than CAPE ( 3 ) . Furthermore, assays of multivalent compounds showed that inhibitory activity of caffeates is not proportional to the number of caffeoyl groups present in a compound . Although most of the caffeoyl esters synthesized in these studies had excellent and similar 5‐LO inhibition potential in HEK293 cell lysates, large variability in inhibition was found when performing assays on whole cells .…”

“…HEK293 cells stably co‐transfected with a pcDNA3.1 vector expressing 5‐LO and a pBUDCE4.1 vector expressing 5‐LO activating protein (FLAP) were utilized to screen compounds for 5‐LO inhibition.…”

“…It is therefore assumed that caffeic acid‐based compounds, which generally possess radical scavenging and antioxidant properties, derive their actions from redox interactions with this ferric iron, uncoupling the redox cycle necessary for LTs biosynthesis . Supporting this hypothesis is the finding that cinnamic acid analogs of CAPE ( 3 ) or of other caffeoyl‐based 5‐LO inhibitors, lacking the redox‐active phenolic hydroxyl groups, lose all 5‐LO inhibitory activity . However, antioxidant activity is not sufficient to assure efficient 5‐LO inhibition in complex systems: caffeic acid ( 2 ) and the amide analog of CAPE ( 3 ), which are roughly equipotent with CAPE ( 3 ) in radical scavenging assays, possess far lower inhibitory activity in PMNL and whole blood assays than CAPE ( 3 ) .…”