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Title: nido-Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase-2

Journal Article · · ChemMedChem
 [1];  [2];  [1];  [3];  [2];  [2];  [4];  [2];  [1]
  1. Univ. Leipzig (Germany)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. Univ. Leipzig (Germany); Rheinische Friedrich-Wilhelms-Univ. Bonn (Germany)
  4. Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
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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. Furthermore, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Inst. of General Medical Sciences
Grant/Contract Number:
AC02‐06CH11357; CA89450; P41 GM103403
OSTI ID:
1236266
Journal Information:
ChemMedChem, Vol. 11, Issue 2; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 51 works
Citation information provided by
Web of Science

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Cited By (13)

CarbORev-5901: The First Carborane-Based Inhibitor of the 5-Lipoxygenase Pathway journal June 2017
Carborane-Based Analogues of 5-Lipoxygenase Inhibitors Co-inhibit Heat Shock Protein 90 in HCT116 Cells journal December 2018
Isomeric Carborane Neuromuscular Blocking Agents journal April 2019
(N,Se) and (Se,N,Se) Ligands Based on Carborane and Pyridine Fragments - Reactivity of 2,6-[(1′-Me-1′,2′- closo -C 2 B 10 H 10 )SeCH 2 ] 2 C 5 H 3 N towards Copper and Silver: (N,Se) and (Se,N,Se) Ligands Based on Carborane and Pyridine Fragments - Reactivity of 2,6-[(1′-Me-1′,2′-closo-C2B10H10)SeCH2]2C5H3N towards Copper an journal May 2017
Binding of indomethacin methyl ester to cyclooxygenase-2. A computational study journal June 2018
Nanoparticle-based formulation of metallacarboranes with bovine serum albumin for application in cell cultures journal January 2020
Structure–activity relationships for the synthesis of selective cyclooxygenase 2 inhibitors: an overview (2009–2016) journal January 2017
Antiproliferative activity of (η 6 -arene)ruthenacarborane sandwich complexes against HCT116 and MCF7 cell lines journal January 2017
New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies journal January 2019
Carborane RAFT agents as tunable and functional molecular probes for polymer materials journal January 2019
Half- and mixed-sandwich metallacarboranes for potential applications in medicine journal April 2019
Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy—A Hypothesis-Driven Review journal April 2016
Focus on Chemistry of the 10-Dioxane-nido-7,8-dicarba-undecahydrido Undecaborate Zwitterion; Exceptionally Easy Abstraction of Hydrogen Bridge and Double-Action Pathways Observed in Ring Cleavage Reactions with OH− as Nucleophile journal February 2020

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