Phenylethynylbenzenesulfonamide Regioisomers Strongly and Selectively Inhibit the Transmembrane, Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Over the Cytosolic Isoforms I and II

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5892-6. doi: 10.1016/j.bmcl.2011.07.090. Epub 2011 Jul 30.

Abstract

A series of compounds incorporating regioisomeric phenylethynylbenzenesulfonamide moieties has been investigated for the inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the milliomolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. The position of the sulfamoyl group with respect to the alkyne functionality, and the nature of the moieties substituting the second aromatic ring were the principal structural features influencing CA inhibition. The para-sulfamoyl-substituted derivatives were effective inhibitors of CA IX and XII, the meta-substituted regioisomers of CA I, IX and XII, whereas the ortho-substituted sulfonamides were weak inhibitors of CA I, II and IX, but inhibited significantly CA XII.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / metabolism*
  • Carbonic Anhydrase I / antagonists & inhibitors
  • Carbonic Anhydrase I / chemistry
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrases / chemistry
  • Carbonic Anhydrases / metabolism*
  • Cytosol / enzymology
  • Drug Screening Assays, Antitumor
  • Humans
  • Isoenzymes / chemistry*
  • Isoenzymes / metabolism
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • phenylethynylbenzenesulfonamide
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII