Design, synthesis and evaluation of N-substituted saccharin derivatives as selective inhibitors of tumor-associated carbonic anhydrase XII

Bioorg Med Chem. 2014 Mar 15;22(6):1821-31. doi: 10.1016/j.bmc.2014.01.056. Epub 2014 Feb 10.

Abstract

A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with KIs ranging between 11 and 390 nM, whereas they were inactive against both CA I (KIs >50 μM) and II (K(I)s ranging between 39.1 nM and 50 μM). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones.

Keywords: Cyclic tertiary sulfonamides; N-alkylation; Saccharin; Selective carbonic anhydrase XII inhibitors.

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
  • Drug Design*
  • Humans
  • Molecular Structure
  • Saccharin / chemical synthesis
  • Saccharin / chemistry
  • Saccharin / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Carbonic Anhydrases
  • carbonic anhydrase XII
  • Saccharin