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

Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti‐LTs activity through the inhibition of 5‐lipoxygenase (5‐LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design an...

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Published in:Chemical biology & drug design 2017-04, Vol.89 (4), p.514-528
Main Authors: Doiron, Jérémie A., Leblanc, Luc M., Hébert, Martin J. G., Levesque, Natalie A., Paré, Aurélie F., Jean‐François, Jacques, Cormier, Marc, Surette, Marc E., Touaibia, Mohamed
Format: Article
Language:English
Subjects:
5‐lipoxygenase inhibitor
antileukotriene
antiradical
Caffeic Acids - chemistry
Caffeic Acids - pharmacology
CAPE
Carbon-13 Magnetic Resonance Spectroscopy
Free Radical Scavengers - pharmacology
HEK293 Cells
Humans
Lipoxygenase Inhibitors - chemistry
Lipoxygenase Inhibitors - pharmacology
Mass Spectrometry
Molecular Docking Simulation
Neutrophils - drug effects
Phenylethyl Alcohol - analogs & derivatives
Phenylethyl Alcohol - chemistry
Phenylethyl Alcohol - pharmacology
Proton Magnetic Resonance Spectroscopy
Structure-Activity Relationship
Thapsigargin - pharmacology
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Summary:Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti‐LTs activity through the inhibition of 5‐lipoxygenase (5‐LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5‐LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a–i and 5a–i, respectively) were synthesized by Sonogashira and Heck cross‐coupling reactions to probe the effects of flexibility and aryl substitution on 5‐LO inhibition. Caffeoyl alcohol and ethers (6, 7a–b) as well as caffeoyl aldehyde and ketones (8a–e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC50 of 10–30 μm). After preliminary anti‐LTs activity screening in HEK293 cell models, 5‐LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration‐dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a–b being roughly eight‐, seven‐, and 16‐fold more potent than Zileuton, with IC50 values of 0.36, 0.43, and 0.18 μm, respectively. A series of caffeic acid phenethyl ester (CAPE) analogs was synthesized and screened in vitro for their ability to inhibit 5‐lipoxygenase (5‐LO) along with 2,2‐diphenyl‐1‐picrylhydrazyl free radical scavenging assay. Many screened compounds outperformed CAPE in concentration‐dependent assays on HEK293 cell models and human polymorphonuclear leukocytes, caffeoyl ethers 7a–b being roughly sevenfold and 16‐fold more potent than Zileuton, the only 5‐LO inhibitor currently approved for human therapy.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.12874