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

Este artículo fue portada de la revista. Artículo dedicado al Prof. José Luis García Ruano en ocasión de su 65 cumpleaños.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.We thank Ria Van Berwaer for excellent technical assistance. We also thank the Spanish MEC/MICINN (Project SAF2009-13914- C02), the Comunidad de Madrid (Projects BIPEDD-CM ref. S-BIO- 0214-2006 and BIPEDD-2-CM ref. S-2010/BMD-2457), and the KU Leuven (GOA No. 10/014) for financial support.Peer reviewe