Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides.

Abstract

The inhibition of the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isozyme has been investigated with a series of aromatic and heterocyclic sulfonamides, including the six clinically used derivatives acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide and brinzolamide. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and IV (membrane-bound) were also provided for comparison. A very interesting and unusual inhibition profile against CA IX with these sulfonamides has been observed. Several nanomolar (K(I)-s in the range of 14-50 nM) CA IX inhibitors have been detected, both among the aromatic (such as orthanilamide, homosulfonilamide, 4-carboxy-benzenesulfonamide, 1-naphthalenesulfonamide and 1,3-benzenedisulfonamide derivatives) as well as the heterocylic (such as 1,3,4-thiadizole-2-sulfonamide, etc.) sulfonamides examined. Because CA IX is a highly active isozyme predominantly expressed in tumor tissues with poor prognosis of disease progression, this finding is very promising for the potential design of CA IX-specific inhibitors with applications as anti-tumor agents.

• Authors: Daniela Vullo, Marco Franchi, Enzo Gallori, Jaromir Pastorek, Andrea Scozzafava, Silvia Pastorekova, Claudiu T Supuran
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 13 Issue 6 Pg. 1005-9 (Mar 24 2003) ISSN: 0960-894X [Print] England
• PMID: 12643899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Heterocyclic Compounds
• Hydrocarbons, Aromatic
• Isoenzymes
• Neoplasm Proteins
• Sulfonamides
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Animals
• Antigens, Neoplasm (metabolism)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, pharmacology)
• Carbonic Anhydrases (metabolism)
• Cattle
• Heterocyclic Compounds (chemical synthesis, chemistry, pharmacology)
• Humans
• Hydrocarbons, Aromatic (chemical synthesis, chemistry, pharmacology)
• Isoenzymes (antagonists & inhibitors)
• Kinetics
• Neoplasm Proteins (metabolism)
• Neoplasms (enzymology)
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)