title: Synthesis and evaluation of fluorobenzoylated di- and tripeptides as inhibitors of cyclooxygenase-2 (COX-2).
abstract: A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Canada.
authors.forename: Sai Kiran
authors.initials: SK
authors.lastname: Sharma
authors.forename: Baker Jawabrah
authors.initials: BJ
authors.lastname: Al-Hourani
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Jonathan Y
authors.initials: JY
authors.lastname: Mane
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
authors.forename: Vickie
authors.initials: V
authors.lastname: Baracos
authors.forename: Mavanur
authors.initials: M
authors.lastname: Suresh
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019817:Benzoic Acid / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry; D006860:Hydrogen Bonding; D051379:Mice; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004151:Dipeptides; D009842:Oligopeptides; D005461:Fluorine; D019817:Benzoic Acid; D051546:Cyclooxygenase 2