Carbonic Anhydrase Inhibitors: Inhibition of the Tumor-Associated Isozyme IX With Aromatic and Heterocyclic Sulfonamides

Bioorg Med Chem Lett. 2003 Mar 24;13(6):1005-9. doi: 10.1016/s0960-894x(03)00091-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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