Synthesis of N'-phenyl-N-hydroxyureas and investigation of their inhibitory activities on human carbonic anhydrases

Bioorg Chem. 2018 Aug:78:1-6. doi: 10.1016/j.bioorg.2018.02.029. Epub 2018 Mar 1.

Abstract

A series of N'-phenyl-N-hydroxyureas has been prepared by reacting hydroxylamine with aromatic isocyanates. These compounds were investigated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1), considering four physiologically relevant isoforms, the cytosolic isoforms hCA I and II, and tumor associated, transmembrane isoforms hCA IX and XII. The new compounds reported here did not inhibit the widespread cytosolic isoforms hCA I and II, but they inhibited the tumor associated isoforms with interesting potencies. The most effective inhibitors showed KIs ranging between 72.8 and 78.9 nM against hCA IX and between 6.9 and 7.2 against hCA XII, making them of interest as candidates for antitumor studies.

Keywords: Carbonic anhydrase; Hypoxic tumors; Inhibitor; N′-phenyl-N-hydroxyurea.

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Hydroxyurea / analogs & derivatives
  • Hydroxyurea / chemistry
  • Hydroxyurea / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Carbonic Anhydrases
  • Hydroxyurea