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Title: Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides
Authors: McGuigan, Christopher ×
Bourdin, Claire
Derudas, Marco
Hamon, Nadège
Hinsinger, Karen
Kandil, Sahar
Madela, Karolina
Meneghesso, Silvia
Pertusati, Fabrizio
Serpi, Michaela
Slusarczyk, Magdalena
Chamberlain, Stanley
Kolykhalov, Alexander
Vernachio, John
Vanpouille, Christophe
Introini, Andrea
Margolis, Leonid
Balzarini, Jan #
Issue Date: Oct-2013
Series Title: European Journal of Medicinal Chemistry vol:70 pages:326-340
Article number: S0223-5234(13)00628-4
Abstract: We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by (31)P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.
URI: 
ISSN: 0223-5234
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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