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

• Published in: Journal of medicinal chemistry Vol. 43; no. 5; pp. 1029 - 1033
• Main Authors: Cohen, Jonathan F, Elberling, James A, DeMaster, Eugene G, Lin, Renee C, Nagasawa, Herbert T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.03.2000; Amer Chemical Soc
• Subjects: Acetaldehyde - metabolism; Alcoholism and acute alcohol poisoning; Animals; Biological and medical sciences; Cell-Free System; Cells, Cultured; Chemistry, Medicinal; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Ethanol - metabolism; Life Sciences & Biomedicine; Liver - cytology; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Penicillamine - analogs & derivatives; Penicillamine - chemical synthesis; Penicillamine - chemistry; Penicillamine - pharmacology; Pharmacology & Pharmacy; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Toxicology; HEMOGLOBIN; ALCOHOLIC PATIENTS; INHIBITION; LIVER-INJURY; MECHANISM; ALDEHYDE DEHYDROGENASE; RATS; ETHANOL; BLOOD-ACETALDEHYDE; ADDUCTS; Ethanol; Rat; Rodentia; Alcohol; Detoxication; Aldehyde; In vitro; Biological activity; Acetaldehyde; Vertebrata; Mammalia; Hepatocyte; Sulfur peptide; Animal; Chelating agent; Dipeptides; Peptide synthesis; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9902741

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.