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Carbonic Anhydrase Inhibitors: Cloning, Characterization, and Inhibition Studies of the Cytosolic Isozyme III With Sulfonamides

Carbonic Anhydrase Inhibitors: Cloning, Characterization, and Inhibition Studies of the Cytosolic Isozyme III With Sulfonamides

Isao Nishimori, Tomoko Minakuchi, Saburo Onishi, Daniela Vullo, Alessandro Cecchi, Andrea Scozzafava, Claudiu T Supuran

Bioorg Med Chem. 2007 Dec 1;15(23):7229-36.

PMID: 17826101

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1217201892	Zonisamide Related Compound C		1217201-89-2	Price

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