4.5 Article

Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX

Journal

CHEMPLUSCHEM
Volume 86, Issue 3, Pages 352-363

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cplu.202000574

Keywords

anti-tumor agents; carbonic anhydrase IX; carboranes; cobalt; enzyme inhibitors

Funding

  1. Czech Science Foundation [1827648S]
  2. European Regional Development Fund [CZ.02.1.01/0.0/0.0/16_019/0000729]
  3. Czech Academy of Sciences [L200321851]

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A series of derivatives based on cobalt bis(dicarbollide)(1-) anion were reported, which can inhibit CAIX with subnanomolar inhibition constants and high selectivity. The compound with n=3 and two substituents in a rac-arrangement showed the best inhibitory properties. X-ray crystallography was used to study the interactions of these compounds with the active site of CAIX on the structural level.
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. Puremeso-andrac-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 withn= 3 and two substituents present inrac-arrangement withK(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.

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