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

0524603 - ÚOCHB 2021 RIV FR eng J - Článek v odborném periodiku
Dvořanová, J. - Kugler, Michael - Holub, Josef - Šícha, Václav - Das, V. - Nekvinda, Jan - El Anwar, Suzan - Havránek, M. - Pospíšilová, Klára - Fábry, M. - Král, V. - Medvedíková, M. - Matějková, Stanislava - Lišková, B. - Gurská, S. - Džubák, P. - Brynda, J. - Hajdúch, M. - Grüner, Bohumír - Řezáčová, Pavlína
Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX.
European Journal of Medicinal Chemistry. Roč. 200, Aug 15 (2020), č. článku 112460. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA ČR(CZ) GA18-27648S; GA ČR(CZ) GA15-05677S; GA TA ČR(CZ) TE01020028; GA MŠMT(CZ) LM2015064
Grant ostatní: AV ČR(CZ) L200321851
Program: Program podpory perspektivníchlidských zdrojů - postdoktorandů
Institucionální podpora: RVO:61388963 ; RVO:61388980
Klíčová slova: anti-tumor agents * carbonic anhydrase IX * carboranes * dicarbollide * enzyme inhibitors * drug penetration * multicellular spheroids
Obor OECD: Biochemistry and molecular biology; Inorganic and nuclear chemistry (UACH-T)
Impakt faktor: 6.514, rok: 2020
Způsob publikování: Omezený přístup
https://www.sciencedirect.com/science/article/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 anti-cancer 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 Ki 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.
Trvalý link: http://hdl.handle.net/11104/0308946