Design and synthesis of glutathione analogues.

摘要

lutathione (GSH) conjugation, mediated by the glutathione S-transferases (GSTs), is an important detoxication reaction, although cases are known where glutathione-dependent bioactivation has resulted in increased toxicity. In an effort to understand the mechanism of catalysis a series of GSH analogues with modifications at the ;Several tripeptides were then synthesized by replacing the L-cysteinyl-moiety of GSH with other amino acids, including D-serine, L-alanine, L-threonine, DL-;Significant progress was made in designing potential affinity labels, including the ;As a separate part of the dissertation, a study was also undertaken to improve the synthesis and isolation of the glutathionyl- and L-cysteinyl-conjugates of acetaminophen. These putative toxic conjugates were synthesized by a phase-transfer catalyzed reaction between the amino acid or peptide and N-acetyl-p-benzoquinone imine (NAPQI). The products were isolated in excellent yields following a single purification step, using reversed-phase flash chromatography (RPFC). Acetaminophen is believed to manifest its toxic effects via NAPQI, involving covalent binding to the cysteinyl residues of essential proteins in the liver and kidney. These conjugates will now be more readily available for further study of these putative protein targets. An improved synthesis of NAPQI is also described.;The initial part of the study was the investigation of the ways and means needed to modify the