Phosphate Chemical Probes Designed for Location Specific Inhibition of Intracellular Carbonic Anhydrases.
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.
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Gregory M
GM
Rankin
Polo Scientifico, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Via della Lastruccia 3, Rm. 188, 50019 Sesto Fiorentino, Florence, Italy.
Daniela
D
Vullo
Polo Scientifico, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Via della Lastruccia 3, Rm. 188, 50019 Sesto Fiorentino, Florence, Italy.
Claudiu T
CT
Supuran
Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Sally-Ann
SA
Poulsen
D000086:Acetazolamide / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D002463:Cell Membrane Permeability; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D012439:Saccharin / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*
C000603805:1-(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; C000603806:2,3,4-tri-O-acetyl-6-O-(((bis((2-((2,2-dimethylpropionyl)sulfanyl)ethoxy))phosphoryloxy)ethyl))glucopyranosylsulfonamide; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D015335:Molecular Probes; D011355:Prodrugs; D013449:Sulfonamides; C000603804:cycloSal-(1-(4-(4-(aminosulfonyl)phenyl)-1H-1,2,3-triazole)-2,3,4-tri-O-acetylglucopyranosyl-6)-phosphate; D019298:Glucose-6-Phosphate; D002256:Carbonic Anhydrases; D012439:Saccharin; D000086:Acetazolamide