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

0540961 - ÚOCHB 2022 RIV DE eng J - Článek v odborném periodiku
Grüner, B. - Kugler, Michael - El Anwar, S. - Holub, J. - Nekvinda, J. - Bavol, D. - Růžičková, Z. - Pospíšilová, Klára - Fábry, M. - Král, V. - Brynda, J. - Řezáčová, Pavlína
Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX.
ChemPlusChem. Roč. 86, č. 3 (2021), s. 352-363. ISSN 2192-6506. E-ISSN 2192-6506
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: anti-tumor agents * carbonic anhydrase IX * carbones * cobalt * enzyme inhibitors
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 3.210, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1002/cplu.202000574

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.
Trvalý link: http://hdl.handle.net/11104/0318544