Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21282
Título: Dipeptide derivatives of AZT
Synthesis, chemical stability, activation in human plasma, hPEPT1 affinity, and antiviral activity
Autor: Santos, Cledir
Morais, Jose
Gouveia, Luis
de Clercq, Erik
Pannecouque, Christophe
Nielsen, Carsten Uhd
Steffansen, Bente
Moreira, Rui
Gomes, Paula
Palavras-chave: Chemistry, Medicinal
Pharmacology & Pharmacy
Data: 2008
Citação: CHEMMEDCHEM. - Vol. 3, n. 6 (JUN 2008), p. 970-978
Resumo: 5'-O-Dipeptide ester prodrugs of antiviral zidovudine (AZT) were designed to target the human intestinal oligopeptide transporter, hPEPT1, and were evaluated for their stability at pH 74 in buffer and in human plasma, affinity toward hPEPT1, cytotoxicity, and antiretroviral activity. The dipeptide esters of AZT undergo cyclization in buffer at pH 7.4 to release the parent drug at a rate that depends on the size of the side chains of the peptide carrier; the prodrug is considerably more stable if bulky beta-branched amino acids such as IIe and Val are present, particularly as C-terminal residues. Incubation in human plasma showed that most of the dipeptide esters of AZT release the parent drug through two aminopeptidase-mediated pathways: 1) stepwise cleavage of each of the amino acids and 2) direct cleavage of the dipeptide-drug ester bond. However, the plasma hydrolysis of Gly-Gly-AZT and Phe-Gly-AZT showed only direct cleavage of the dipeptide-drug ester bond. Substrate half-lives in plasma were again remarkably high when hydrophobic beta-bronched amino acids (Val, lie) were present. The esters were also good substrates for the intestinal oligopeptide transporter hPEPT1 in vitro, with Val-Gly-AZT and Val-Ala-AZT presenting the highest affinity toward the transporter (IC50: 0.20 and 0.15 mM, respectively). The AZT dipeptide esters were assayed against the IIIB and ROD strains of HIV, and their cytotoxicity was evaluated in MT-4 cells. The selectivity index of the prodrugs was two- to threefold higher than that of AZT for all compounds analyzed. These results point to the potential of dipeptide-based carriers for the development of effective antiviral drug-delivery systems. Val-Ala-AZT appears to combine chemical stability with good affinity for the hPEPT1 transporter and on improved cytotoxicity/antiretroviral index relative to AZT.
URI: http://hdl.handle.net/10451/21282
DOI: http://dx.doi.org/10.1002/cmdc.200800012
ISSN: 1860-7179
Aparece nas colecções:FF - Produção Científica 2000-2009

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