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Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides
journal contribution
posted on 2023-06-08, 21:49 authored by Christopher McGuigan, Claire Bourdin, Marco Derudas, Nadège Hamon, Karen Hinsinger, Sahar Kandil, Karolina Madela, Silvia Meneghesso, Fabrizio Pertusati, Michaela Serpi, Magdalena Slusarczyk, Stanley Chamberlain, Alexander Kolykhalov, John Vernachio, Christophe Vanpouille, Andrea Introini, Leonid Margolis, Jan BalzariniWe 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 31P 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.
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Publication status
- Published
Journal
European Journal of Medicinal ChemistryISSN
0223-5234Publisher
ElsevierExternal DOI
Volume
70Page range
326-340Department affiliated with
- Chemistry Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-22Usage metrics
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