Carborane-Based Inhibitors of Carbonic Anhydrase IX 

Introduction

Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyse interconversion between carbon dioxide and the bicarbonate ion. They play key roles in many physiological processes but immense experimental evidences also suggests the involvement of CAs in various pathological processes. Many human CA isozymes are thus recognized as diagnostic and therapeutic targets.

Materials/methods

The sulfamide compounds were prepared from their respective amine or ammonium carborane derivatives. The compounds were tested in vitro for inhibition of the human CA isozymes CAII and CAIX using a colorimetric enzymatic assay. Crystal structures of selected active compounds in complex with CAII isoenzyme and CAII mutated to be CAIX-like were determined.

Results and conclusions

Our results suggest that carboranebased compounds are promising lead structures for the development of inhibitors of CA isozymes. Until today about 50 compounds have been prepared and tested in vitro. Our experiments demonstrated that various types of hydrophobic, space-filling carborane clusters can be accommodated in the CA active site and that substitution with an appropriately attached sulfamide group and other substituents leads to compounds with high selectivity for the cancer-specific CAIX isozyme over the widespread CAII isozyme. Crystal structures confirmed our hypothesis that three-dimensional scaffolds could be efficiently used in CA inhibitors and provided structural information that can be applied to the structure-based design of specific CAIX inhibitors. Toxicity and pharmacokinetics study are available for 3 selected compounds and their effect on tumor growth and progression in vivo in mouse models is now in progress.