title: Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors.
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 (IC50of 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 IC50values of 0.36, 0.43, and 0.18 μm, respectively.
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Jérémie A
authors.initials: JA
authors.lastname: Doiron
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Luc M
authors.initials: LM
authors.lastname: Leblanc
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Martin J G
authors.initials: MJ
authors.lastname: Hébert
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Levesque
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Aurélie F
authors.initials: AF
authors.lastname: Paré
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Jean-François
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Cormier
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Surette
authors.affiliation: Département de chimie et biochimie, Université de Moncton, Moncton, NB, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
mesh_terms: D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D009504:Neutrophils / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002109:Caffeic Acids; D016166:Free Radical Scavengers; D016859:Lipoxygenase Inhibitors; D019284:Thapsigargin; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: 
  CAPE
  ; 5-lipoxygenase inhibitor; antileukotriene; antiradical