Truncated phosphonated C-1′-branched N,O-nucleosides: A new class of antiviral agents

Roberto Romeo,Caterina Carnovale,Salvatore V Giofrè,Giovanni Romeo,Beatrice Macchi,Caterina Frezza,Francesca Marino-Merlo,Venerando Pistarà,Ugo Chiacchio

doi:10.1016/j.bmc.2012.03.047

Roberto Romeo, Caterina Carnovale + Show 7 more

Open Access

https://doi.org/10.1016/j.bmc.2012.03.047

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Abstract

Truncated phosphonated C-1′-branched N,O-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology, starting from N-methyl-C-(diethoxyphosphoryl)nitrone 7. Preliminary biological assays show that β-anomers are able to inhibit HIV in vitro infection at concentrations in the micromolar range. Higher SI values with respect to AZT indicated that the compounds were endowed with low cytotoxicity.

Highlights

Natural psicofuranosyl nucleosides, bearing a hydroxymethyl group at the anomeric carbon atom, have been reported to possess different and relevant biological activities.[1]
N,O-psiconucleosides 4 constitute a particular class of modified psiconucleosides where an isoxazolidine system mimics the ribose ring of natural nucleosides and a hydroxymethyl group is linked at the anomeric carbon atom.[5]
In connection with our work addressed to the search of new and potent antiviral agents, we have extended our interest to the synthesis of the new generation of truncated phosphonated C-10branched N,O-nucleosides

Summary

Introduction

Natural psicofuranosyl nucleosides, bearing a hydroxymethyl group at the anomeric carbon atom, have been reported to possess different and relevant biological activities.[1]. In the field of nucleoside analogs, N,O-modified nucleosides have been proved to efficiently block the in vitro and in vivo virus infections caused by HIV, HBV, and HTLV-1.17–22 Following intracellular phosphorylation to their 50-triphosphate forms, they are able to serve as chain terminators, acting as inhibitors in the viral reverse transcription reaction.[18,19] Several strategies to overcome the initial selective phosphorylation step have been designed;[23] in particular, phosphonate analogues,[20] by miming the nucleoside monophosphates, overcome the instability of nucleotides towards phosphodiesterase and enhance the cellular uptake by bypassing the initial phosphorylation step In this context, we have recently reported the synthesis of phosphonated carbocyclic 20-oxa-30-azanucleosides (PCOANS) 5, which have shown to be potent inhibitors of RT of different retroviruses[21] (Fig. 2). To the best of our knowledge, no example of this kind of compounds has been reported in the literature until now

Chemistry

Biological results

Conclusion

Experimental section

Synthesis of isoxazolidines 9 and 10

Biological assay