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Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

McGuigan, Christopher ORCID:, Bourdin, Claire, Derudas, Marco, Hamon, Nadege, Hinsinger, Karen, Kandil, Sahar ORCID:, Madela, Karolina, Meneghesso, Silvia, Pertusati, Fabrizio ORCID:, Serpi, Michaela ORCID:, Slusarczyk, Magdalena ORCID:, Chamberlain, Stanley, Kolykhalov, Alexander, Vernachio, John, Vanpouille, Christophe, Introini, Andrea, Margolis, Leonid and Balzarini, Jan 2013. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides. European Journal of Medicinal Chemistry 70 , pp. 326-340. 10.1016/j.ejmech.2013.09.047

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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 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Nucleoside analogs; Antiviral; Anticancer; Phosphorodiamidates; Prodrugs
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 30 March 2016
Last Modified: 20 Jun 2024 20:40

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