Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol.
Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37 degrees C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N- and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclization-activated prodrugs.
Santos
Cledir
C
CIQUP, Departamento de Química, Faculdade de Ciências do Porto, P-4169-007 Porto, Portugal.
Mateus
Maria Luísa
ML
dos Santos
Ana Paula
AP
Moreira
Rui
R
de Oliveira
Eliandre
E
Gomes
Paula
P
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
D004151:Dipeptides; D004952:Esters; D011355:Prodrugs; D000082:Acetaminophen; D005978:Glutathione