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Title: Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides
Contributor(s): Wilkinson, Brendan (author)orcid ; Innocenti, Alessio (author); Vullo, Daniela (author); Supuran, Claudiu T (author); Poulsen, Sally-Ann (author)
Publication Date: 2008
DOI: 10.1021/jm701426t
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Abstract: A library of glycoconjugate benzene sulfonamides have been synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant human carbonic anhydrase (hCA) isozymes: hCA I, II, and tumor-associated IX. Our synthetic strategy directly links the known CA pharmacophore (ArSO2NH2) to a sugar 'tail' moiety through a rigid 1,2,3-triazole linker unit using the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction or 'click chemistry'. Many of the glycoconjugates were potent CA inhibitors and exhibited some isozyme selectivity. In particular, the methyl-D-glucuronate triazoles 6 and 14 were potent inhibitors of hCA IX (Kis 9.9 and 8.4 nM, respectively) with selectivity also favoring this isozyme. Other exceptional compounds included the deprotected B-D-ribofuranosyl triazole 15 and α-D-mannosyl triazole 17, which were potent and selective hCA II inhibitors (Ki 7.5 nM and Ki 2.3 nM, respectively). Collectively, the results confirm that modification of ring size, stereochemical configuration, and chain length in the sugar tail moiety of glycoconjugate CA inhibitors permits tunable potency and selectivity that may constitute an important avenue for the future development of efficacious and selective CA-based therapeutics.
Publication Type: Journal Article
Source of Publication: Journal of Medicinal Chemistry, 51(6), p. 1945-1953
Publisher: American Chemical Society
Place of Publication: United States of America
ISSN: 0022-2623
Field of Research (FOR): 030401 Biologically Active Molecules
030503 Organic Chemical Synthesis
030499 Medicinal and Biomolecular Chemistry not elsewhere classified
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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