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 beta, beta-disubstituted-beta-mercapto-alpha-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-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 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-alpha-aminoisobutyric acid) were able to reduce this AcH level by approximately one-third.
Cohen
J F
JF
Medical Research Laboratories, VA Medical Centers, Minneapolis, Minnesota 55417, USA.
Elberling
J A
JA
DeMaster
E G
EG
Lin
R C
RC
Nagasawa
H T
HT
D000079:Acetaldehyde / Q000378:metabolism*; D000818:Animals; D002474:Cell-Free System; D002478:Cells, Cultured; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D004151:Dipeptides; C406236:penicillamyl-alpha-aminoisobutyric acid; C406235:penicillamyl-beta-alanine; C406234:penicillamylglycine; D000431:Ethanol; D010396:Penicillamine; D000079:Acetaldehyde