Sulfonamides Incorporating Boroxazolidone Moieties Are Potent Inhibitors of the Transmembrane, Tumor-Associated Carbonic Anhydrase Isoforms IX and XII

Bioorg Med Chem Lett. 2011 May 15;21(10):2975-9. doi: 10.1016/j.bmcl.2011.03.055. Epub 2011 Mar 21.

Abstract

A new series of sulfonamides was synthesized by the reaction of the boroxazolidone complex of l-lysine with isothiocyanates incorporating sulfamoyl moieties and diverse organic scaffolds. The obtained thioureas have been investigated as inhibitors of four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. Inhibition between the low nanomolar to the micromolar range has been observed against them, with several low nanomolar and tumor-CA selective inhibitors detected. These boron-containing compounds might be useful for the management of hypoxic tumors overexpressing hCA IX/XII by means of boron neutron capture therapy, a technique not investigated so far with inhibitors of this enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Boron Compounds / chemistry*
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Enzyme Activation / drug effects*
  • Humans
  • Molecular Structure
  • Neoplasm Proteins / antagonists & inhibitors
  • Oxazolidinones / chemistry*
  • Protein Isoforms
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Boron Compounds
  • Carbonic Anhydrase Inhibitors
  • Neoplasm Proteins
  • Oxazolidinones
  • Protein Isoforms
  • Sulfonamides
  • boroxazolidone
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII