32623-88-4Relevant academic research and scientific papers
Sulfonamido carboranes as highly selective inhibitors of cancer-specific carbonic anhydrase IX
Das, Viswanath,El Anwar, Suzan,Holub, Josef,Kugler, Michael,Nekvinda, Jan,?ezá?ová, Pavlína,?ícha, Václav,Brynda, Ji?í,D?ubák, Petr,Dvo?anová, Jana,Fábry, Milan,Grüner, Bohumír,Gurská, Soňa,Hajdúch, Marián,Havránek, Miroslav,Král, Vlastimil,Li?ková, Barbora,Matějková, Stanislava,Medvedíková, Martina,Pospí?ilová, Klára
supporting information, (2020/06/08)
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.
Reactions of prop-2-yne-1-sulphonyl chloride with α-morpholinostyrene
Bradamante,Del Buttero,Maiorana
, p. 612 - 615 (2007/10/09)
The reaction between prop-2-yne-1-sulphonyl chloride and α-morpholinostyrene was performed (a) in the presence of an equimolar amount of triethylamine at 0° to give 4-acetyl-3-phenyl-2H-thiet 1,1-dioxide (7) and 1-morpholino-1-phenyl-3-thiahex-1-en-5-yne 3,3-dioxide (3) or the corresponding 3-thiahex-1-en-5-one dioxide (6), depending on the work-up conditions; and (b) at -30° with triethylamine and sulphonyl chloride in a 3:1 ratio to give 3-morpholino-3-phenyl-2-vinylidenethietan 1,1 -dioxide (11) and the open-chain sulphone (6). The origin of the products is discussed. Compound (11) and 1-morpholino-1-phenyl-3-thiahexa-1,4,5-triene 3,3-dioxide (10) are shown to be the possible precursors of the sulphones (7) and (6), respectively.
