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 earlie r pioneered the development of beta,beta-disubstituted-beta-mercapto-alpha- amino acids as AcH-sequestering agents. We now report the synthesis of a se ries of N-terminal dipeptides of D(-)-penicillamine, prepared from the synt hon 3-formyl-2,2,5,5-tetramethylthiazolidine-4S-carboxylic acid (3), a cycl ized N-protected derivative of D(-)-penicillamine. These dipeptides were eq ually or more effective than penicillamine in trapping AcH in a cell-free s ystem. In experiments using a hepatocyte culture system, two of the dipepti des, D-penicillamylglycine (6a) and D-penicillamyl-beta-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 cyanamid e tan inhibitor of aldehyde dehydrogenase) in the incubation medium resulte d in a 45-fold increase in ethanol-derived AcH; nevertheless, dipeptides 8a and 6c (D-penicillamyl-alpha-aminoisobutyric acid) were able to reduce thi s AcH level by approximately one-third.