title: nido-Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase-2.
abstract: Carbaboranes are increasingly studied as pharmacophores, particularly as replacements for aromatic systems. However, especially ortho-carbaborane is prone to degradation of the cluster, which hampers biological application. This study demonstrates that deboronation of the cluster may not only lead to a more active analogue, but can also improve the solubility and stability of a carbaborane-containing inhibitor. Notably, introduction of a nido-dicarbaborate cluster into the cyclooxygenase (COX) inhibitor indomethacin results in remarkably increased inhibitory potency and selectivity for COX-2 relative to the respective phenyl analogue. The first crystal structure of a carbaborane-containing inhibitor bound to COX-2 further reveals a novel binding mode for the inhibitor that is strikingly different from that of indomethacin. These results indicate that nido-dicarbaborate is a promising pharmacophore that exhibits properties which are also highly beneficial for its introduction into other inhibitor classes.
authors.affiliation: Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.
authors.forename: Wilma
authors.initials: W
authors.lastname: Neumann
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 23rdAvenue South & Pierce, Nashville, TN 37232, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.
authors.forename: Menyhárt B
authors.initials: MB
authors.lastname: Sárosi
authors.affiliation: Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.|Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, 53121, Bonn, Germany.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Scholz
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 23rdAvenue South & Pierce, Nashville, TN 37232, USA.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 23rdAvenue South & Pierce, Nashville, TN 37232, USA.
authors.forename: Kebreab
authors.initials: K
authors.lastname: Ghebreselasie
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA).|Northeastern Collaborative Access Team, Argonne National Laboratory, Argonne, IL 60439, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 23rdAvenue South & Pierce, Nashville, TN 37232, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany. hey@uni-leipzig.de.
authors.forename: Evamarie
authors.initials: E
authors.lastname: Hey-Hawkins
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001880:Boranes / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D012756:Sheep; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001880:Boranes; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; D007213:Indomethacin
keywords: carbaboranes; carboranes; cyclooxygenases; drug design; enzymes; inhibitors; selectivity