Cyclic tertiary sulfamates: selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives

Eur J Med Chem. 2014 Sep 12:84:240-6. doi: 10.1016/j.ejmech.2014.07.014. Epub 2014 Jul 8.

Abstract

Carbonic anhydrase (hCA) IX and XII isoforms are over-expressed both in primary and in metastatic cell lines of hypoxic tumors and are innovative targets for cancer diagnosis and treatment. On the basis of the importance of the pharmacophoric sulfamate moiety (bioisostere of the sulfonamide group) present in the structure of recent human CA inhibitors, we designed N-alkylated and O-alkylated derivatives of acesulfame, a cyclic tertiary sulfamate, assessing the inhibitory activity against the ubiquitous isoforms hCA I and II and the cancer-related isoforms hCA IX and XII. All derivatives were nanomolar inhibitors, with some of them possessing an outstanding selectivity towards the tumor-associated hCA IX and/or hCA XII isoforms.

Keywords: Acesulfame derivatives; Anticancer agents; N-alkylation; O-alkylation; Selective hCA IX/hCAXII inhibitors; Sulfamate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacology*
  • Thiazines / chemical synthesis
  • Thiazines / chemistry
  • Thiazines / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Protein Isoforms
  • Sulfonic Acids
  • Thiazines
  • sulfamic acid
  • Carbonic Anhydrases
  • acetosulfame