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.

Apigenex s r o Poděbradská 59 186 180 66 Prague 9 Czech Republic

Cancer Research Czech Republic Hněvotínská 5 77900 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Natural Science Charles University Hlavova 2030 12800 Prague 2 Czech Republic

Institute of Inorganic Chemistry of the Czech Academy of Sciences 250 68 Řež Czech Republic

Institute of Molecular and Translational Medicine Olomouc Hněvotínská 1333 5 77900 Olomouc Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Videňská 1083 142 20 Prague 4 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague 6 Czech Republic

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$a Dvořanová, Jana $u Institute of Molecular and Translational Medicine, Olomouc, Hněvotínská 1333/5, 77900, Olomouc, Czech Republic; Cancer Research Czech Republic, Hněvotínská 5, 77900, Olomouc, Czech Republic

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$a Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX / $c J. Dvořanová, M. Kugler, J. Holub, V. Šícha, V. Das, J. Nekvinda, S. El Anwar, M. Havránek, K. Pospíšilová, M. Fábry, V. Král, M. Medvedíková, S. Matějková, B. Lišková, S. Gurská, P. Džubák, J. Brynda, M. Hajdúch, B. Grüner, P. Řezáčová

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$a 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.

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$a Kugler, Michael $u Institute of Molecular Genetics of the Czech Academy of Sciences, Videňská 1083, 142 20, Prague 4, Czech Republic; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16610, Prague 6, Czech Republic

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$a Nekvinda, Jan $u Institute of Inorganic Chemistry of the Czech Academy of Sciences, 250 68, Řež, Czech Republic; Department of Organic Chemistry, Faculty of Natural Science, Charles University, Hlavova 2030, 12800, Prague 2, Czech Republic

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$a Brynda, Jiří $u Institute of Molecular Genetics of the Czech Academy of Sciences, Videňská 1083, 142 20, Prague 4, Czech Republic. Electronic address: brynda@img.cas.cz

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