New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies

Bioorg Med Chem. 2015 Jul 1;23(13):2975-81. doi: 10.1016/j.bmc.2015.05.013. Epub 2015 May 14.

Abstract

Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII.

Keywords: Molecular modelling; Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry*
  • Carbonic Anhydrase I / chemistry*
  • Carbonic Anhydrase II / chemistry*
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrases / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Assays
  • Humans
  • Molecular Docking Simulation
  • Probenecid / analogs & derivatives
  • Probenecid / chemical synthesis*
  • Protein Binding
  • Sensitivity and Specificity
  • Structure-Activity Relationship

Substances

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