Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives.
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Ilies MA, Vullo D, Pastorek J, Scozzafava A, Ilies M, Caproiu MT, Pastorekova S, Supuran CT
Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives.
J Med Chem. 2003 May 22;46(11):2187-96.
- PubMed ID
- 12747790 [ View in PubMed]
- Abstract
Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 5-{[(4-AMINO-3-CHLORO-5-FLUOROPHENYL)SULFONYL]AMINO}-1,3,4-THIADIAZOLE-2-SULFONAMIDE Carbonic anhydrase 2 Ki (nM) 0.3 7.5 22 Details Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 7.5 22 Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 7.5 22 Details Brinzolamide Carbonic anhydrase 2 Ki (nM) 3 7.5 22 Details Diclofenamide Carbonic anhydrase 1 Ki (nM) 1200 7.5 22 Details Diclofenamide Carbonic anhydrase 2 Ki (nM) 38 7.5 22 Details Dorzolamide Carbonic anhydrase 1 Ki (nM) 50000 7.5 22 Details Dorzolamide Carbonic anhydrase 2 Ki (nM) 9 7.5 22 Details Ethoxzolamide Carbonic anhydrase 1 Ki (nM) 25 7.5 22 Details Ethoxzolamide Carbonic anhydrase 2 Ki (nM) 8 7.5 22 Details Methazolamide Carbonic anhydrase 1 Ki (nM) 50 7.5 22 Details Methazolamide Carbonic anhydrase 2 Ki (nM) 14 7.5 22 Details