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Carborane derivatives as inhibitors of human carbonic anhydrase isoenzymes

INTRODUCTION: 
Human carbonic anhydrases (CAs) play important roles in many pathological processes and several CA isoenzymes thus represent diagnostic and therapeutic targets. The development of certain isoform-specifi c sulfonamide inhibitor is still an important task in current medicine.

TECHNOLOGY (INVENTION) DESCRIPTION: 
We have developed unique selective CAIX inhibitors with anticancer properties based on carborane scaffold to structure-assisted design of novel and original inhibitors targeting therapeutically relevant isoenzymes of human carbonic anhydrase.

ADVANTAGES OVER EXISTING SOLUTIONS: 
Novelty, in brief, is represented by the intended elaboration of carborane, heteroborane and metallaborane compounds as active-site inhibitors of CA isoenzymes. All currently used inhibitors anhydrase inhibitors contain a sulfonamide or a sulfamate moiety connected to so called ‘ring structure’ which is usually a 5- or 6-membered aromatic ring or conjugated ring system containing nitrogen, oxygen, and/ or sulfur heteroatoms. The ‘ring structure’ bears characteristics or functionality which modulates the affi nity toward certain CA isoform. The use of three-dimensional boron cluster is a novel approach in development of isoform-specifi c CA inhibitors. Selected sulfamides incorporating cluster with inhibitory effects toward CAs (IC50 values in low micromolar and submicromolar range, some of the inhibitors being more than 50-times more selective toward the tumor specifi c CAIX than for CAII abundantly present in normal tissues).

DEVELOPMENT STATUS (STAGE): 
Laboratory scale, data on cell lines, crystal structure, limited ADME/Tox data, in vivo pharmacology and pharmacodynamics.

IP PROTECTION STATUS: 
Patent protection: WO 2013/060307 EP 2771015 US 2014/303390

TECHNOLOGY / IP OWNERS : 
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences Institute of Molecular Genetics, Czech Academy of Sciences Institute of Inorganic Chemistry, Czech Academy of Sciences Palacky University Olomouc - Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry