Discovery of new 2, 5-disubstituted 1,3-selenazoles as selective human carbonic anhydrase IX inhibitors with potent anti-tumor activity

Eur J Med Chem. 2018 Sep 5:157:1214-1222. doi: 10.1016/j.ejmech.2018.08.096. Epub 2018 Sep 3.

Abstract

A series of disubstituted selenazole derivatives was synthetized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV, VA, VB and IX, involved in a variety of diseases including glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors. The investigated compounds showed potent inhibition against the tumor-associated transmembrane hCA IX, with KIs in the subnanomolar - low nanomolar range, and were evaluated for their effects on cell viability against the human prostate (PC3) and breast (MDA-MB-231) cancer cell lines, showing effective anti-tumor activity. These selenazoles are interesting leads for the development of new, isoform-selective CA IX inhibitors.

Keywords: Carbonic anhydrase; Inhibitor; Metalloenzymes; Selenazole; Selenium; Tumors.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carbonic Anhydrase IX / antagonists & inhibitors*
  • Carbonic Anhydrase IX / metabolism
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Carbonic Anhydrase IX