This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space-filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure-activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster-containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster-containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).

Institute of Inorganic Chemistry of the Czech Academy of Sciences Hlavní Husinec 1001 25068 Řež Czech Republic

Institute of Molecular and Translational Medicine Hněvotínská 1333 5 77900 Olomouc Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 14220 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague Czech Republic

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Carbon-Substituted Amines of the Cobalt Bis(dicarbollide) Ion: Stereochemistry and Acid-Base Properties

Chemistry of Carbon-Substituted Derivatives of Cobalt Bis(dicarbollide)(1-) Ion and Recent Progress in Boron Substitution

Electrochemistry of Cobalta Bis(dicarbollide) Ions Substituted at Carbon Atoms with Hydrophilic Alkylhydroxy and Carboxy Groups