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  • Title: Carbonic anhydrase inhibitors: transepithelial transport of thioureido sulfonamide inhibitors of the cancer-associated isozyme IX is dependent on efflux transporters.
    Author: Vullo D, Steffansen B, Brodin B, Supuran CT, Scozzafava A, Nielsen CU.
    Journal: Bioorg Med Chem; 2006 Apr 01; 14(7):2418-27. PubMed ID: 16321542.
    Abstract:
    Sulfonamides and their derivatives inhibit the catalytic activity of carbonic anhydrases (CA, EC 4.2.1.1). Isozyme IX (CA IX) is a transmembrane isoform with the active site oriented toward the extracellular space. CA IX was recently shown to be a drug target, and it is highly overexpressed in hypoxic tumors with limited distribution in normal tissues. The present report deals with the drug design, synthesis, and biological investigation of a group of thioureido sulfonamides, which have been obtained by reaction of isothiocyanate-substituted aromatic sulfonamides with amines. These compounds have potent inhibitory properties against CA IX with K(I) values in the range of 10-37 nM and P(app)values > 0.34 x 10(-6) cm/s for the absorptive transepithelial transport in Caco-2 cells. In Caco-2 cells, one of these compounds (A6) was shown to be a substrate for efflux transporters such as P-glycoprotein (P-gp). P-gp activity is not likely to be rate-limiting for intestinal absorption, but might be useful when targeting hypoxic tumors expressing both P-gp and CA IX.
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