title: Prodrugs of L-cysteine as protective agents against acetaminophen-induced hepatotoxicity. 2-(Polyhydroxyalkyl)- and 2-(polyacetoxyalkyl)thiazolidine-4(R)-carboxylic acids.
abstract: Eight prodrugs of L-cysteine (1a-h) were synthesized by the condensation of the sulfhydryl amino acid with naturally occurring aldose monosaccharides containing three, five, and six carbon atoms. The resulting 2-(polyhydroxyalkyl)thiazolidine-4(R)-carboxylic acids (TCAs) are capable of releasing L-cysteine and the sugars by nonenzymatic ring opening and hydrolysis. Thus, when added to rat hepatocyte preparations in vitro, these TCAs (1.0 mM) raised cellular glutathione (GSH) levels 1.2-2.1-fold relative to controls. On the basis of this finding, the cysteine prodrugs were tested as protective agents against acetaminophen-induced hepatotoxicity in a mouse model. The TCA derived from D-ribose and L-cysteine (RibCys, 1d) showed the greatest therapeutic promise of the series, with a 100% (12/12) survival profile compared to 17% without treatment. However, the degree of stimulation of GSH production in rat hepatocytes by these prodrugs did not correlate with the extent of protection afforded in mice, suggesting that pharmacokinetic parameters must supervene in vivo. To evaluate the effect of increased lipid solubility, we prepared prodrugs 2a-c by using peracetylated aldehydic sugars in the condensation reaction. These compounds, however, displayed acute toxicity to mice, possibly due to liberation of the acetylated sugars themselves. Nevertheless, the efficacy of the unacetylated TCAs, and RibCys (1d) in particular, suggests that the prodrug approach for the delivery of L-cysteine to the liver represents a viable means of augmenting existing detoxication mechanisms in protecting cells against xenobiotic substances that are bioactivated to toxic, reactive metabolites.
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455.
authors: J C
authors: JC
authors: Roberts
authors: H T
authors: HT
authors: Nagasawa
authors: R T
authors: RT
authors: Zera
authors: R F
authors: RF
authors: Fricke
authors: D J
authors: DJ
authors: Goon
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D019328:Buthionine Sulfoximine; D003545:Cysteine / Q000627:therapeutic use*; D004358:Drug Therapy; D005978:Glutathione / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines
chemical_list: D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; C003438:thiazolidine-4-carboxylic acid; D005978:Glutathione; D003545:Cysteine