Carbonic anhydrase IX (CAIX) is an enzyme expressed on the surface of cells in hypoxic tumors. It plays a role in regulation of tumor pH and promotes thus tumor cell survival and occurrence of metastases. Here, derivatives of the cobalt bis(dicarbollide)(1-) anion are reported that are based on substitution at the carbon sites of the polyhedra by two alkylsulfonamide groups differing in the length of the aliphatic connector (from C1 to C4, n=1-4), which were prepared by cobalt insertion into the 7-sulfonamidoalkyl-7,8-dicarba-nido-undecaborate ions. Pure meso- and rac-diastereoisomeric forms were isolated. The series is complemented with monosubstituted species (n=2). Synthesis by a direct method furnished similar derivatives (n=2, 3), which are chlorinated at the B(8,8') boron sites. All compounds inhibited CAIX with subnanomolar inhibition constants and showed high selectivity for CAIX. The best inhibitory properties were observed for the compound with n= 3 and two substituents present in rac-arrangement with Ki =20 pM and a selectivity index of 668. X-ray crystallography was used to study interactions of these compounds with the active site of CAIX on the structural level.

Department of General and Inorganic Chemistry Faculty of Chemical Technology University of Pardubice Studentská 573 532 10 Pardubice Czech Republic

Department of Synthesis Institute of Inorganic Chemistry of the Czech Academy of Sciences 250 68 Řež Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 166 10 Prague Czech Republic

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

Cobalt Bis-Dicarbollide Enhances Antibiotics Action towards Staphylococcus epidermidis Planktonic Growth Due to Cell Envelopes Disruption

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