title: Discovery and biological evaluation of novel 1,4-benzoquinone and related resorcinol derivatives that inhibit 5-lipoxygenase.
abstract: 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the discovery and biological evaluation of novel series of 1,4-benzoquinones and respective resorcinol derivatives that efficiently inhibit human 5-LO, with little effects on other human lipoxygenases. SAR analysis revealed that the potency of the compounds strongly depends on structural features of the lipophilic residues, where bulky naphthyl or dibenzofuran moieties favor 5-LO inhibition. Among the 1,4-benzoquinones, compound Ig 5-[(2-naphthyl)methyl]-2-hydroxy-2,5-cyclohexadiene-1,4-dione potently blocked 5-LO activity in cell-free assays with IC50 = 0.78 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 2.3 μM. Molecular docking studies suggest a concrete binding site for Ig in 5-LO where select π-π interactions along with hydrogen bond interactions accomplish binding to the active site of the enzyme. Together, our study reveals novel valuable 5-LO inhibitors with potential for further preclinical assessment as anti-inflammatory compounds.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, SA, Italy. Electronic address: rfilosa@unisa.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.forename: Polamarasetty
authors.initials: P
authors.lastname: Aparoy
authors.forename: Anja M
authors.initials: AM
authors.lastname: Schaible
authors.forename: Susann
authors.initials: S
authors.lastname: Luderer
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.forename: Carmen
authors.initials: C
authors.lastname: Petronzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.forename: Mario
authors.initials: M
authors.lastname: de Rosa
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins; D012118:Resorcinols; C004532:quinone; D001094:Arachidonate 5-Lipoxygenase; C031389:resorcinol
keywords: 5-Lipoxygenase; Benzoquinone; Leukotriene; Molecular docking; Resorcinol