Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX

0511423 - ÚOCHB 2020 RIV US eng J - Journal Article
Grüner, B. - Brynda, Jiří - Das, V. - Šícha, V. - Štěpánková, J. - Nekvinda, J. - Holub, J. - Pospíšilová, Klára - Fábry, M. - Pachl, Petr - Král, V. - Kugler, Michael - Mašek, V. - Medvedíková, M. - Matějková, Stanislava - Nová, A. - Lišková, B. - Gurská, S. - Džubák, P. - Hajdúch, M. - Řezáčová, Pavlína
Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX.
Journal of Medicinal Chemistry. Roč. 62, č. 21 (2019), s. 9560-9575. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LM2015064
Institutional support: RVO:61388963
Keywords : cobalt bis(1,2-dicarbollide) * carborane complexes * medicinal chemistry
OECD category: Biochemistry and molecular biology
Impact factor: 6.205, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b00945

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme that regulates pH in hypoxic tumors and promotes tumor cell survival. Its expression is associated with the occurrence of metastases and poor prognosis. Here, we present nine derivatives of the cobalt bis(dicarbollide)(1−) anion substituted at the boron or carbon sites by alkysulfamide group(s) as highly specific and selective inhibitors of CAIX. Interactions of these compounds with the active site of CAIX were explored on the atomic level using protein crystallography. Two selected derivatives display subnanomolar or picomolar inhibition constants and high selectivity for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives had a time-dependent effect on the growth of multicellular spheroids of HT-29 and HCT116 colorectal cancer cells, facilitated penetration and/or accumulation of doxorubicin into spheroids, and displayed low toxicity and showed promising pharmacokinetics and a significant inhibitory effect on tumor growth in syngenic breast 4T1 and colorectal HT-29 cancer xenotransplants.
Permanent Link: http://hdl.handle.net/11104/0301695