title: Carbonic anhydrase inhibitors: transepithelial transport of thioureido sulfonamide inhibitors of the cancer-associated isozyme IX is dependent on efflux transporters.
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.
authors.affiliation: Molecular Biopharmaceutics, Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, 2-Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Bente
authors.initials: B
authors.lastname: Steffansen
authors.forename: Birger
authors.initials: B
authors.lastname: Brodin
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Carsten Uhd
authors.initials: CU
authors.lastname: Nielsen
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects*; D001692:Biological Transport; D018938:Caco-2 Cells; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases