N-Terminal Dipeptides of d(−)-Penicillamine as Sequestration Agents for Acetaldehyde

Since acetaldehyde (AcH), a toxic oxidation product of ethanol, may play an etiologic role in the initiation of alcoholic liver disease, we had earlier pioneered the development of β,β-disubstituted-β-mercapto-α-amino acids as AcH-sequestering agents. We now report the synthesis of a series of N-terminal dipeptides of d(−)-penicillamine, prepared from the synthon 3-formyl-2,2,5,5-tetramethylthiazolidine-4S-carboxylic acid (3), a cyclized N-protected derivative of d(−)-penicillamine. These dipeptides were equally or more effective than penicillamine in trapping AcH in a cell-free system. In experiments using a hepatocyte culture system, two of the dipeptides, d-penicillamylglycine (6a) and d-penicillamyl-β-alanine (6d), at 1/20 the molar concentration of ethanol, lowered the concentration of ethanol-derived AcH by 79% and 84%, respectively, at 2 h. The presence of cyanamide (an inhibitor of aldehyde dehydrogenase) in the incubation medium resulted in a 45-fold increase in ethanol-derived AcH; nevertheless, dipeptides 6a and 6c (d-penicillamyl-α-aminoisobutyric acid) were able to reduce this AcH level by approximately one-third.