title: Phenylsulphonyl urenyl chalcone derivatives as dual inhibitors of cyclo-oxygenase-2 and 5-lipoxygenase.
abstract: Two series of phenylsulphonyl urenyl chalcone derivatives (UCH) with various patterns of substitution were tested for their effects on nitric oxide (NO) and prostaglandin E2 (PGE2) overproduction in RAW 264.7 macrophages. None of the tested compounds reduced NO production more than 50% at 10 microM but most of them inhibited the generation of PGE2 with IC50 values under the micromolar range. Me-UCH 1, Me-UCH 5, Me-UCH 9, Cl-UCH 1, and Cl-UCH 9 were selected to evaluate their influence on human leukocyte functions and eicosanoids generation. These derivatives selectively inhibited cyclo-oxygenase-2 (COX-2) activity in human monocytes being Me-UCH 5 the most potent (IC50 0.06 microM). Selected compounds also reduced leukotriene B4 synthesis in human neutrophils by a direct inhibition of 5-lipoxygenase (5-LO) activity, with IC50 values from 0.5 to 0.8 microM. In addition, lysosomal enzyme secretion, such as elastase or myeloperoxidase as well as superoxide generation in human neutrophils were also reduced in a similar range. Our findings indicate that UCH derivatives exert a dual inhibitory effect on COX-2/5-LO activity. The profile and potency of these compounds may have relevance for the modulation of the inflammatory and nociceptive responses with reduction of undesirable side-effects associated with NSAIDs.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Av. Vicent Andrés Estellés s/n 46100 Burjassot, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Araico
authors.forename: M C
authors.initials: MC
authors.lastname: Terencio
authors.forename: M J
authors.initials: MJ
authors.lastname: Alcaraz
authors.forename: J N
authors.initials: JN
authors.lastname: Domínguez
authors.forename: C
authors.initials: C
authors.lastname: León
authors.forename: M L
authors.initials: ML
authors.lastname: Ferrándiz
mesh_terms: D000818:Animals; D002460:Cell Line; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047188:Chalcones; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D015232:Dinoprostone