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: Daniela Vullo, Bente Steffansen, Birger Brodin, Claudiu T Supuran, Andrea Scozzafava, Carsten Uhd Nielsen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 7 Pg. 2418-27 (Apr 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16321542 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Isoenzymes
• Sulfonamides
• Carbonic Anhydrase I
• Carbonic Anhydrase II
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Antigens, Neoplasm (drug effects)
• Biological Transport
• Caco-2 Cells
• Carbonic Anhydrase I (antagonists & inhibitors)
• Carbonic Anhydrase II (antagonists & inhibitors)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Carbonic Anhydrases (drug effects)
• Humans
• Isoenzymes (antagonists & inhibitors)
• Molecular Structure
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured