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Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme

AuthorsDiez-Torrubia, Alberto ; Cabrera, Silvia ; Castro, Sonia de ; García-Aparicio, Carlos ; Mulder, Gwenn; De Meester, Ingrid; Camarasa Rius, María José ; Balzarini, Jan; Velázquez, Sonsoles ; Diez-Torrubia, Alberto
Solid-phase synthesis
Issue Date2013
CitationEuropean Journal of Medicinal Chemistry 70: 456- 468 (2013)
AbstractWe 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 solid-phase 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2013.10.001
Identifiersdoi: 10.1016/j.ejmech.2013.10.001
issn: 0223-5234
e-issn: 1768-3254
Appears in Collections:(IQM) Artículos
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