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Title: Dipeptidyl peptidase IV-activated prodrugs of anti-varicella zoster virus bicyclic nucleoside analogues containing different self-cleavage spacer systems
Authors: Diez-Torrubia, Alberto ×
Cabrera, Silvia
De Meester, Ingrid
Camarasa, María-José
Balzarini, Jan
Velázquez, Sonsoles #
Issue Date: Sep-2012
Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
Series Title: ChemMedChem vol:7 issue:9 pages:1612-22
Article number: 10.1002/cmdc.201200295
Abstract: A 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.
URI: 
ISSN: 1860-7179
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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