Carbonic anhydrase inhibitors: inhibition of human cytosolic isozymes I and II and tumor-associated isozymes IX and XII with S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides

Bioorg Med Chem. 2008 Apr 1;16(7):3933-40. doi: 10.1016/j.bmc.2008.01.034. Epub 2008 Jan 26.

Abstract

A series of S-substituted 4-chloro-2-mercapto-5-methyl-benzenesulfonamides has been investigated as inhibitors of four isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic, ubiquitous isozymes CA I and II, as well as the transmembrane, tumor-associated isozymes CA IX and XII. The new derivatives were inefficient inhibitors of isoform I (K(I)s in the range of 2.7-18.7 microM) but generally had low nanomolar affinity for the inhibition of the other three isoforms (K(I)s in the range of 2.4-214 nM against hCA II; 1.4-47.5 nM against hCA IX, and 1.7-569 nM against hCA XII, respectively). Some selectivity for the inhibition of the tumor-associated versus the cyctosolic isoform II with some of these compounds has also been evidenced. As CA IX is an important marker of tumor hypoxia and its predictive, prognostic, and druggability potentials for designing antitumor therapies were recently validated, detection of selective, potent CA IX inhibitors may be relevant in the fight against cancers overexpressing CA isozymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / chemistry
  • Carbonic Anhydrases / metabolism*
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Humans
  • Hydrocarbons, Chlorinated / chemical synthesis
  • Hydrocarbons, Chlorinated / chemistry
  • Hydrocarbons, Chlorinated / pharmacology*
  • Isoenzymes / metabolism
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Neoplasms / enzymology*
  • Neoplasms / pathology
  • Protein Folding
  • Sequence Alignment
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Hydrocarbons, Chlorinated
  • Isoenzymes
  • Sulfhydryl Compounds
  • Sulfonamides
  • benzenesulfonamide
  • Carbonic Anhydrases