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Dipeptidyl Peptidase IV-Activated Prodrugs of Anti- Varicella Zoster Virus Bicyclic Nucleoside Analogues Containing Different Self-Cleavage Spacer Systems

AuthorsDiez-Torrubia, Alberto ; Cabrera, Silvia ; De Meester, Ingrid; Camarasa Rius, María José ; Balzarini, Jan; Velázquez, Sonsoles
dipeptidyl peptidase IV
self-cleavage spacers
Issue Date2012
PublisherJohn Wiley & Sons
CitationChemMedChem 7 : 1612–1622 (2012)
AbstractA new type of double prodrug of the antiviral family of bicyclic nucleoside analogues (BCNA) bearing cyclization self-cleavage spacers between the Val-Pro dipeptide sequence as well as the parent compound were synthesized and evaluated with regard to activation by the DPPIV/CD26 enzyme and for their stability in human and bovine serum. In buffer solution, carbamate and ester prodrugs were found to be chemically stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val-Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val-Val dipeptide as a self-cleavage spacer released substantial amounts of the BCNA parent drug at the basolateral side of Caco-2 cell cultures and exhibited 15- to 20-fold increased bioavailability in mice relative to the poorly bioavailable parent compound.
DescriptionEste artículo fue portada de la revista. Artículo dedicado al Prof. José Luis García Ruano en ocasión de su 65 cumpleaños.
Publisher version (URL)http://dx.doi.org/10.1002/cmdc.201200295
Appears in Collections:(IQM) Artículos
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