期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 70, 期 -, 页码 456-468出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.10.001
关键词
Acyclovir; Antiviral; Prodrug; Peptide; Dipeptidyl peptidase IV; Solid-phase synthesis
资金
- Spanish MEC/MICINN [SAF2009-13914-C02, SAF2012-39760-C02]
- Comunidad de Madrid [BIPEDD-2-CM, S-2010/BMD-2457]
- KU Leuven [10/014]
- Spanish Ministry of Science and Innovation
We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solidphase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug. (C) 2013 Elsevier Masson SAS. All rights reserved.
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