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.

Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell

“…To render cells more reduced, medium was supplemented with NAC or with GlcCys, ProCys, or RibCys, three polyhydroxyalkyl thiazolidine carboxylic acid compounds. These pro-cysteine drugs contribute to glutathione biosynthesis when taken up by cells and their thialozolidine ring is opened enzymatically (26). Thus, the activity of GlcCys, ProCys, and RibCys is more specifically targeted to intracellular thiol pools than is NAC.…”

Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production

“…9) Several 2-monosubstituted thiazolidine-4-carboxylic acids, which are cyclic Cys derivatives with a masked sulfhydryl group, have been used as protective agents to liberate Cys non-enzymatically at physiological pH and temperature. [10][11][12][13] Several 2-(substituted phenyl) thiazolidine-4-carbxylic acid derivatives have been investigated as agents for inhibition of melanogenesis or as tyrosinase inhibitors. [14][15][16] However, some of these compounds have the disadvantage of liberating toxic aldehyde upon degradation.…”

Hepatoprotection by L‐cysteine‐glutathione mixed disulfide, a sulfhydryl‐modified prodrug of glutathione

“…Postadministration of NAC, a prodrug of L-cysteine, or other cysteine prodrugs that have been sulfhydryl-modified, effectively protects mice against this ACP-induced hepatotoxicity [5][6][7].…”