PMID: 8997900Nov 1, 1996Paper

Phosphono analogues of glutathione as new inhibitors of glutathione S-transferases

Archiv der Pharmazie
T Kunze

Abstract

Phosphono-analogues of glutathione containing the O = P(OR)2 moiety in place of the cysteinyl residue CH2SH 1a-1d were prepared by solution phase peptide synthesis. Benzyl, benzyloxy-carbonyl, and tert-butyl protecting groups were used to mask the individual amino acid functional groups. The formation of peptide bonds was achieved by the usual peptide synthesis via activation of carboxylic functions with cyclohexylcarbodiimide and subsequent reaction with free amino groups. The thus obtained, fully-protected peptides were each purified by normal phase column chromatography. Deprotection was accomplished by hydrogenolysis and by treatment with HBr/acetic acid yielding the desired phosphonic acid diester 1a-1d. The inhibition of the glutathione conjugation of 1-chloro-2,4-dinitrobenzene by human placental glutathione S-transferase was studied by determining the IC50 values of the new glutathione analogues. The IC50 values were 291 microM, 139 microM, 64 microM, and 21 microM for the dimethyl, diethyl, diisopropyl, and di-n-butyl esters, respectively. The results clearly show that the formal substitution of the glutathione thiol function by phosphonic acid esters leads to a new class of glutathione S-transferase inhibitors. Furthe...Continue Reading

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Citations

Oct 31, 2000·Journal of the Neurological Sciences·S WinterM Weller
Aug 17, 1999·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·M IlyasW F Bodmer
Jan 17, 2020·Critical Reviews in Toxicology·Patrick E Hanna, M W Anders
Feb 7, 2020·G3 : Genes - Genomes - Genetics·Elizabeth B BrownStephanie M Rollmann
Apr 12, 2020·Applied and Environmental Microbiology·Luis R Paniagua VoirolMonika Hilker
May 7, 1999·Il Farmaco·G LucenteF Pinnen
Dec 12, 2001·Bioorganic & Medicinal Chemistry·Danny BurgGerard J Mulder

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