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nido ‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2
Author(s) -
Neumann Wilma,
Xu Shu,
Sárosi Menyhárt B.,
Scholz Matthias S.,
Crews Brenda C.,
Ghebreselasie Kebreab,
Banerjee Surajit,
Marnett Lawrence J.,
HeyHawkins Evamarie
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500199
Subject(s) - pharmacophore , chemistry , cyclooxygenase , stereochemistry , potency , selectivity , combinatorial chemistry , pharmacology , biochemistry , enzyme , in vitro , biology , catalysis
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.