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

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. Potency boost: Replacement of a phenyl moiety in indomethacin with a nido‐dicarbaborate group results in a compound with a novel binding mode and markedly increased inhibitory activity and selectivity for COX‐2, with a concomitant increase in stability and water solubility, while maintaining strong hydrophobic interactions in the binding site of the enzyme. This shows nido‐dicarbaborate to be a promising pharmacophore for a variety of inhibitors.