Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX

0531266 - ÚMG 2021 RIV FR eng J - Journal Article
Dvořanová, J. - Kugler, Michael - Holub, J. - Šícha, V. - Das, V. - Nekvinda, J. - El Anwar, S. - Havránek, M. - Pospíšilová, K. - Fábry, Milan - Král, Vlastimil - Medvědiková, M. - Matějková, S. - Lišková, B. - Gurská, S. - Dzubak, P. - Brynda, Jiří - Hajduch, M. - Gruner, B. - Řezáčová, P.
Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX.
European Journal of Medicinal Chemistry. Roč. 200, August (2020), č. článku 112460. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR(CZ) GA15-05677S
Institutional support: RVO:68378050
Keywords : Anti-tumor agents * Carbonic anhydrase IX * Carboranes * Dicarbollide * Enzyme inhibitors * Drug penetration * Multicellular spheroids
OECD category: Medicinal chemistry
Impact factor: 6.514, year: 2020
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/abs/pii/S0223523420304311?via%3Dihub

Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anticancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms, n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a K-i value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum. (C) 2020 Elsevier Masson SAS. All rights reserved.
Permanent Link: http://hdl.handle.net/11104/0309958