Carbonic Anhydrase Inhibitors: The First Selective, Membrane-Impermeant Inhibitors Targeting the Tumor-Associated Isozyme IX

Bioorg Med Chem Lett. 2004 Feb 23;14(4):869-73. doi: 10.1016/j.bmcl.2003.12.029.


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.

MeSH terms

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


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