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Structure-activity Relationship of Caffeic Acid Phenethyl Ester Analogs as New 5-lipoxygenase Inhibitors

Structure-activity Relationship of Caffeic Acid Phenethyl Ester Analogs as New 5-lipoxygenase Inhibitors

Jérémie A Doiron, Luc M Leblanc, Martin J G Hébert, Natalie A Levesque, Aurélie F Paré, Jacques Jean-François, Marc Cormier, Marc E Surette, Mohamed Touaibia

Chem Biol Drug Des. 2017 Apr;89(4):514-528.

PMID: 27717142

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP3598263	Caffeoyl alcohol		3598-26-3	Price

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