Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of the cytosolic isozyme III with sulfonamides.
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Nishimori I, Minakuchi T, Onishi S, Vullo D, Cecchi A, Scozzafava A, Supuran CT
Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of the cytosolic isozyme III with sulfonamides.
Bioorg Med Chem. 2007 Dec 1;15(23):7229-36. Epub 2007 Aug 25.
- PubMed ID
- 17826101 [ View in PubMed]
- Abstract
The cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozyme III (hCA III) has been cloned and purified by the GST-fusion protein method. Recombinant pure hCA III had the following kinetic parameters for the CO(2) hydration reaction at 20 degrees C and pH 7.5: k(cat) of 1.3 x 10(4) s(-1) and k(cat)/K(M) of 2.5 x 10(5) M(-1) s(-1), being a slower catalyst for the physiological reaction as compared to the genetically related cytosolic isoforms hCA I and II. An inhibition study with a library of sulfonamides and one sulfamate, some which are clinically used compounds, is reported. hCA III is less prone to be inhibited by these compounds as compared to hCA I and II for which many low nanomolar inhibitors were detected earlier. The best hCA III inhibitors were prontosil, sulpiride, indisulam, benzolamide, aminobenzolamide, and 4-amino-6-chloro-benzene-1,3-disulfonamide which showed K(I)s in the range of 2.3-18.1 microM. Clinically used compounds such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, topiramate, zonisamide, celecoxib, and valdecoxib were less effective hCA III inhibitors, with affinities in the range of 154-2200 microM. This is the first study in which low micromolar hCA III inhibitors are reported.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Brinzolamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Celecoxib Carbonic anhydrase 2 Protein Humans UnknownInhibitorDetails Celecoxib Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Diclofenamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Dorzolamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Ethoxzolamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Methazolamide Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Saccharin Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Sulpiride Carbonic anhydrase 2 Protein Humans UnknownInhibitorDetails Sulpiride Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Topiramate Carbonic anhydrase 1 Protein Humans UnknownInhibitorDetails Topiramate Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails Valdecoxib Carbonic anhydrase 2 Protein Humans UnknownInhibitorDetails Valdecoxib Carbonic anhydrase 3 Protein Humans UnknownInhibitorDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details Acetazolamide Carbonic anhydrase 3 Ki (nM) 236000 N/A N/A Details Brinzolamide Carbonic anhydrase 3 Ki (nM) 110000 N/A N/A Details Celecoxib Carbonic anhydrase 3 Ki (nM) 154000 N/A N/A Details Diclofenamide Carbonic anhydrase 3 Ki (nM) 684000 N/A N/A Details Dorzolamide Carbonic anhydrase 3 Ki (nM) 770000 N/A N/A Details Ethoxzolamide Carbonic anhydrase 3 Ki (nM) 1113000 N/A N/A Details Sulpiride Carbonic anhydrase 3 Ki (nM) 10600 N/A N/A Details Topiramate Carbonic anhydrase 3 Ki (nM) 780000 N/A N/A Details Valdecoxib Carbonic anhydrase 3 Ki (nM) 788000 N/A N/A Details Zonisamide Carbonic anhydrase 3 Ki (nM) 2200000 N/A N/A Details