Phosphate Chemical Probes Designed for Location Specific Inhibition of Intracellular Carbonic Anhydrases

J Med Chem. 2015 Sep 24;58(18):7580-90. doi: 10.1021/acs.jmedchem.5b01228.

Abstract

Chemical probes are small molecules designed to bind to a specific protein and disrupt the proteins function. Although many inhibitors are reported for human carbonic anhydrase (CA) enzymes, few may be considered useful as chemical probes as they exhibit broad action against the 12 catalytically active CA isozymes. In addition, most do not possess an appropriate physicochemical profile to discriminate intracellular CA activity from either global or extracellular CA activity. We report herein the synthesis of three monophosphate CA proinhibitors (compounds 2, 3, and 5) that are derived from cyclosaligenyl (cycloSal) phosphate and S-acyl-2-thioethyl (SATE) phosphate as protecting groups. The proinhibitors are designed as neutral, membrane-permeable compounds that once inside the cell may be hydrolyzed by pH-driven or enzymatic-driven mechanisms to release a negatively charged monophosphate. The resulting monophosphate compound is trapped intracellularly and available for locality specific inhibition of intracellular CAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetazolamide / chemistry
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrases / chemistry*
  • Cell Membrane Permeability
  • Glucose-6-Phosphate / analogs & derivatives*
  • Glucose-6-Phosphate / chemical synthesis
  • Glucose-6-Phosphate / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Intracellular Space / enzymology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Molecular Probes / chemical synthesis
  • Molecular Probes / chemistry*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry*
  • Saccharin / analogs & derivatives
  • Saccharin / chemistry
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*

Substances

  • 1-(4-(4-(aminosulfonyl)phenyl)-1H-1,2,3-triazole)-2,3,4-tri-O-acetyl-6-O-(((bis((2-((2,2-dimethylpropionyl)sulfanyl)ethoxy))phosphoryloxy)ethyl))glucopyranoside
  • 2,3,4-tri-O-acetyl-6-O-(((bis((2-((2,2-dimethylpropionyl)sulfanyl)ethoxy))phosphoryloxy)ethyl))glucopyranosylsulfonamide
  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Molecular Probes
  • Prodrugs
  • Sulfonamides
  • cycloSal-(1-(4-(4-(aminosulfonyl)phenyl)-1H-1,2,3-triazole)-2,3,4-tri-O-acetylglucopyranosyl-6)-phosphate
  • Glucose-6-Phosphate
  • Carbonic Anhydrases
  • Saccharin
  • Acetazolamide