Carbonic Anhydrase Inhibitors. Inhibition of Tumor-Associated Isozyme IX by Halogenosulfanilamide and Halogenophenylaminobenzolamide Derivatives

J Med Chem. 2003 May 22;46(11):2187-96. doi: 10.1021/jm021123s.

Abstract

Two series of halogenated sulfonamides have been prepared. The first consists of mono/dihalogenated sulfanilamides, whereas the second one consists of the mono/dihalogenated aminobenzolamides, incorporating equal or different halogens (F, Cl, Br, and I). These sulfonamides have been synthesized from the corresponding anilines by acetylation (protection of the amino group), chlorosulfonylation, followed either by amidation, or reaction with 5-amino-1,3,4-thiadiazole-2-sulfonamide (and eventually deacetylation). All these compounds, together with the six clinically used sulfonamide inhibitors (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) were investigated as inhibitors of the transmembrane, tumor-associated isozyme carbonic anhydrase (CA) IX. Inhibition data against the classical, physiologically relevant isozymes I, II, and IV were also obtained. CA IX shows an inhibition profile which is generally completely different from those of isozymes I, II, and IV, with potent inhibitors (inhibition constants in the range of 12-40 nM) among both simple aromatic (such as 3-fluoro-5-chloro-4-aminobenzenesulfonamide) as well as heterocyclic compounds (such as acetazolamide, methazolamide, 5-amino-1,3,4-thiadiazole-2-sulfonamide, aminobenzolamide, and dihalogenated aminobenzolamides). This first detailed CA IX inhibition study revealed many interesting leads, suggesting the possibility to design even more potent and eventually CA IX-selective inhibitors, with putative applications as antitumor agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Bromine / chemistry
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / chemistry
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase IV / antagonists & inhibitors
  • Carbonic Anhydrase IV / chemistry
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / chemistry
  • Chlorine / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Iodine / chemistry
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / chemistry
  • Structure-Activity Relationship
  • Sulfanilamides / chemical synthesis
  • Sulfanilamides / chemistry
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Benzene Derivatives
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Sulfanilamides
  • Sulfonamides
  • Chlorine
  • Iodine
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • Carbonic Anhydrase IV
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • Bromine