Chemical and biological analysis of novel thiazolidine prodrugs of L-cysteine

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Title Chemical and biological analysis of novel thiazolidine prodrugs of L-cysteine
Publication Type dissertation
School or College College of Pharmacy
Department Medicinal Chemistry
Author Dominick, Pamela K.
Contributor Cassidy, Pamela Dr.; Jameton, Rachel
Date 2002-05
Description The therapeutic manipulation of glutathione (GSH) levels is important in cases where toxic agents cause GSH depletion. GSH depletion causes deleterious effects inside cells, as this thiol serves may protective roles. One way to increase intracellular GSH level is to supply cysteine, the rate-limiting precursor in GSH biosynthesis. Cysteine is known to be toxic to cells and therefore, cannot be administered directly. To overcome this toxicity, cysteine can be delivered in a produg form. The development of cysteine prodrugs had been found to be clinically relevant, especially during GSH depletion caused by acetaminophen (APAP). One class of cysteine prodrugs, 2-alkyl-thiazolidines, has proven to be useful delivery agents. Described here are four novel 2-alkylthiazolidines. The amide and ethyl ester of 2(R,S)-D-gluco1',2',3,'4',5'-pentahydroxypentylthiazolidine-4(R)-carboxylic acid (GlcCys amide and GlyCys ethyl ester) and 2(R,S)-D-ribo-1',2',3',4'-tetrahydroxybutylthiazolidine-4(r)-carboxylic and (RibCys amide and RibCys ethyl ester) were synthesized and assayed for their protective capabilities. To test compounds against APAP-induced toxicity, a cell assay using HepG2 cells and the toxin 2,6-dimethyl-N-acetyl-p-benzoquinoneimine (2,6-diMeNAPQI), a synthetic analog of a reactive APAP metabolite, was utilized. GlcCys ethyl ester, RibCys amide, and GlcCys amide were proven to protect against 2,6-diMeNAPQI-induced toxicity. This protection was dependent on intracellular process to activate the prodrugs evidenced by their lack of reaction with 2,6-diMeNAPQI in solution. To further the understanding of these and other cysteine prodrugs and to facilitate the study of biological thiols in general, an HPLC assay that allows the concomitant separation and measurement of cysteine and GSH and their oxidized species was developed. This assay showed that the prodrugs elevated cysteine but not GSH levels in HepG2 cells. These results indicate that the novel prodrugs are attractive lead compounds for further analysis as cysteine delivery vehicles to abate the toxicity of APAP overdose.
Type Text
Publisher University of Utah
Subject Physiology; Analysis; Prodrugs
Subject MESH Pharmaceutical Preparations; Glutathione; Cysteine Proteinase Inhibitors
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "The chemical and biological analysis of novel thiazolidine prodrugs of L-cysteine." Spencer S. Eccles Health Sciences Library. Print version of "The chemical and biological analysis of novel thiazolidine prodrugs of L-cysteine." available at J. Willard Marriott Library Special Collection. RM31.5 2002 .D64.
Rights Management © Pamela K. Dominick.
Format application/pdf
Format Medium application/pdf
Format Extent 2,402,812 bytes
Identifier undthes,5087
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 2,402,885 bytes
ARK ark:/87278/s60p11tz
Setname ir_etd
ID 191110
Reference URL https://collections.lib.utah.edu/ark:/87278/s60p11tz
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