Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo

J Med Chem. 2012 Feb 23;55(4):1721-30. doi: 10.1021/jm300031j. Epub 2012 Feb 13.

Abstract

A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glucoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Crystallography, X-Ray
  • Glaucoma / drug therapy*
  • Glaucoma / enzymology
  • Humans
  • Intraocular Pressure / drug effects
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / enzymology
  • Protein Conformation
  • Rabbits
  • Structure-Activity Relationship
  • Thiocarbamates / chemical synthesis*
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Thiocarbamates

Associated data

  • PDB/3P5A