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Design, Synthesis and Biological Evaluation of Phosphorodiamidate Prodrugs of Antiviral and Anticancer Nucleosides

Design, Synthesis and Biological Evaluation of Phosphorodiamidate Prodrugs of Antiviral and Anticancer Nucleosides

Christopher McGuigan, Claire Bourdin, Marco Derudas, Nadège Hamon, Karen Hinsinger, Sahar Kandil, Karolina Madela, Silvia Meneghesso, Fabrizio Pertusati, Michaela Serpi, Magdalena Slusarczyk, Stanley Chamberlain, etc.

Eur J Med Chem. 2013;70:326-40.

PMID: 24177359

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
CS3104408	Abacavir Stereoisomers Mixture			Price

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