title: Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes.
abstract: 5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 = 0.8-2 μM, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 = 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 = 0.21 μM), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highly potent 5-LO-selective lead compound in intact cells that warrants further preclinical evaluation as anti-inflammatory agent.
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Electronic address: rosanna.filosa@unina2.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy; Dermofarma, Via Cortenocera, 82030 S. Salvatore Telesino, BN, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Anja M
authors.initials: AM
authors.lastname: Schaible
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Krauth
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Weinigel
authors.affiliation: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Petronzi
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bruno
authors.affiliation: Department of Experimental Pharmacology, University Federico II of Naples, Naples, Italy.
authors.forename: Fiorentina
authors.initials: F
authors.lastname: Roviezzo
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Spaziano
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.affiliation: Department of Experimental Medicine, University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: De Rosa
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D016227:Benzoquinones / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; C004532:quinone; D001092:Arachidonate 12-Lipoxygenase; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: 5-Lipoxygenase; Arachidonic acid; Benzoquinone; Inflammation; Microsomal prostaglandin E(2) synthase-1