Carbonic Anhydrase Inhibitors. Synthesis of a Novel Series of 5-substituted 2,4-dichlorobenzenesulfonamides and Their Inhibition of Human Cytosolic Isozymes I and II and the Transmembrane Tumor-Associated Isozymes IX and XII

Eur J Med Chem. 2014 Jul 23;82:47-55. doi: 10.1016/j.ejmech.2014.05.039. Epub 2014 May 13.

Abstract

A series of novel 5-substituted 2,4-dichlorobenzenesulfonamides 5a-c, 6a-d, 7a-j and 10a-i have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and tumor-associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed KI values from 349 to 7355 nM, toward hCA II at range of 6.9 to 164 nM, while against hCA IX ranging from 2.8 to 76 nM and against hCA XII in the range of 2.7 to 95 nM. The excellent inhibitory activity against tumor-associated hCA IX was found. The twenty one new compounds displayed a powerful inhibitory potency toward hCA IX (KI = 2.8-21.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). Among them the most potent hCA IX inhibitor 7b (KI = 2.8 nM) was 8.5-fold stronger than IND (KI = 24 nM). Toward tumor-associated hCA XII compounds 6c and 10a (KI = 2.7 and 2.8 nM, respectively) showed a better inhibitory potency than reference sulfonamides MZA and IND (KI = 3.4 nM).

Keywords: 2,4-Dichlorobenzenesulfonamides; Carbonic anhydrase isozymes I, II, IX and XII inhibitors; Synthesis.

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Cell Membrane / enzymology*
  • Dose-Response Relationship, Drug
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Structure
  • Neoplasms / enzymology*
  • Neoplasms / pathology
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Carbonic Anhydrases