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-nidoundecaborate 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 K i = 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.

The most significant result of this study is design and synthesis of boron-cluster-containing compounds that inhibit activity of the cancer-associated enzyme CA IX with picomolar inhibition constants. Moreover,X-ray crystallography,w as used to help understand their interactions at the active site of the enzyme on an atomic level.

Human carbonic anhydrase IX (CA IX), a protein specifically expressed on the surface of solid tumour cells, represents a validated target both for anticancer therapy and diagnostics. We recently identified sulfonamide dicarbaboranes as promising inhibitors of CA IX with favourable activities both in vitro and in vivo. To explain their selectivity and potency, we performed detailed X-ray structural analysis of their interactions within the active sites of CA IX and CA II. Series of compounds bearing various aliphatic linkers between the dicarbaborane cluster and sulfonamide group were examined. Preferential binding towards the hydrophobic part of the active site cavity was observed. Selectivity towards CA IX lies in the shape complementarity of the dicarbaborane cluster with a specific CA IX hydrophobic patch containing V131 residue. The bulky side chain of F131 residue in CA II alters the shape of the catalytic cavity, disrupting favourable interactions of the spherical dicarbaborane cluster.

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