Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX.

Abstract

The inhibition of the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isozyme possessing an extracellular active site has been investigated with a series of positively-charged, pyridinium derivatives of sulfanilamide, homosulfanilamide and 4-aminoethylbenzenesulfonamide. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and IV (membrane-bound) were also provided for comparison. A very interesting inhibition profile against CA IX with these sulfonamides has been observed. Several nanomolar (K(i)'s in the range of 6-54 nM) CA IX inhibitors have also been detected. Because CA IX is a highly active isozyme predominantly expressed in tumor tissues with bad prognosis of disease progression, this finding is very promising for the potential design of CA IX-specific inhibitors with applications as anti-tumor agents. This is the first report of inhibitors that may selectively target CA IX, due to their membrane-impermeability and high affinity for this clinically relevant isozyme.

• Authors: Silvia Pastorekova, Angela Casini, Andrea Scozzafava, Daniela Vullo, Jaromir Pastorek, Claudiu T Supuran
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 4 Pg. 869-73 (Feb 23 2004) ISSN: 0960-894X [Print] England
• PMID: 15012984 (Publication Type: Journal Article)

Chemical References

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

Topics

• Antigens, Neoplasm (drug effects, metabolism)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, pharmacology)
• Carbonic Anhydrases (drug effects, metabolism)
• Humans
• Isoenzymes (antagonists & inhibitors)
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors)
• Sulfonamides (chemical synthesis, pharmacology)