Keywords:

Abstract:

<p>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.</p>