Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IX with triazole-linked O-glycosides of benzene sulfonamides
Author(s)
Wilkinson, Brendan L
Bornaghi, Laurent F
Houston, Todd A
Innocenti, Alessio
Vullo, Daniela
Supuran, Claudiu T
Poulsen, Sally-Ann
Year published
2007
Metadata
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We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 nM and 9.7-107 ...
View more >We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 nM and 9.7-107 nM, respectively was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM), this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.
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View more >We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 nM and 9.7-107 nM, respectively was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM), this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.
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Journal Title
Journal of Medicinal Chemistry
Volume
50
Issue
7
Publisher URI
Subject
Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences