6YKC

Metala-Carborane di-ethyl-sulfonamide (trans isomer) in complex with CA IX mimic

Summary for 6YKC

• Entry DOI: 10.2210/pdb6ykc/pdb
• Related: 6Y3J
• Descriptor: Carbonic anhydrase 2, ZINC ION, Metala-Carborane di-ethyl-sulfonamide, ... (5 entities in total)
• Functional Keywords: carbonic anhydrase, ca inhibitor, lyase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 30302.00

Authors

Kugler, M.,Brynda, J.,Pospisilova, K.,Rezacova, P. (deposition date: 2020-04-06, release date: 2020-09-09, Last modification date: 2024-01-24)

Primary citation

Gruner, B.,Kugler, M.,El Anwar, S.,Holub, J.,Nekvinda, J.,Bavol, D.,Ruzickova, Z.,Pospisilova, K.,Fabry, M.,Kral, V.,Brynda, J.,Rezacova, P.
Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX.
Chempluschem, 86:352-363, 2021

PubMed Abstract: 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 K =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.

PubMed: 32955786
DOI: 10.1002/cplu.202000574

Experimental method

X-RAY DIFFRACTION (1.2 Å)