Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX
Language English Country France Media print-electronic
Document type Journal Article
PubMed
32505851
DOI
10.1016/j.ejmech.2020.112460
PII: S0223-5234(20)30431-1
Knihovny.cz E-resources
- Keywords
- Anti-tumor agents, Carbonic anhydrase IX, Carboranes, Dicarbollide, Drug penetration, Enzyme inhibitors, Multicellular spheroids,
- MeSH
- Antigens, Neoplasm metabolism MeSH
- Neoplasms, Experimental drug therapy metabolism MeSH
- Carbonic Anhydrase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Carbonic Anhydrase IX antagonists & inhibitors metabolism MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Molecular Structure MeSH
- Mice, Inbred BALB C MeSH
- Mice, SCID MeSH
- Mice MeSH
- Breast Neoplasms drug therapy metabolism MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Dogs MeSH
- Recombinant Proteins metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Sulfonamides chemical synthesis chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antigens, Neoplasm MeSH
- CA9 protein, human MeSH Browser
- Carbonic Anhydrase Inhibitors MeSH
- Carbonic Anhydrase IX MeSH
- Antineoplastic Agents MeSH
- Recombinant Proteins MeSH
- Sulfonamides MeSH
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
Institute of Inorganic Chemistry of the Czech Academy of Sciences 250 68 Řež Czech Republic
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