Carbonic anhydrase inhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides.

Article Details

Citation

Wilkinson BL, Bornaghi LF, Houston TA, Innocenti A, Vullo D, Supuran CT, Poulsen SA

Carbonic anhydrase inhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides.

J Med Chem. 2007 Apr 5;50(7):1651-7. Epub 2007 Mar 8.

PubMed ID
17343373 [ View in PubMed
]
Abstract

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 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AcetazolamideCarbonic anhydrase 1Ki (nM)9007.525Details
AcetazolamideCarbonic anhydrase 2Ki (nM)127.525Details
BrinzolamideCarbonic anhydrase 1Ki (nM)157.525Details
BrinzolamideCarbonic anhydrase 2Ki (nM)97.525Details
DiclofenamideCarbonic anhydrase 1Ki (nM)12007.525Details
DiclofenamideCarbonic anhydrase 2Ki (nM)387.525Details
EthoxzolamideCarbonic anhydrase 1Ki (nM)257.525Details
EthoxzolamideCarbonic anhydrase 2Ki (nM)87.525Details
MethazolamideCarbonic anhydrase 1Ki (nM)7807.525Details
MethazolamideCarbonic anhydrase 2Ki (nM)147.525Details