Synthesis and biological evaluation of phosphonated dihydroisoxazole nucleosides

Abstract

Abstract-Phosphonated isoxazolinyl nucleosides have been prepared via 1,3-dipolar cycloaddition reaction of nitrile oxides with corresponding vinyl or allyl nucleobases for antiviral studies. The cytotoxicity, the anti-HSV activity and the RT-inhibitory activity of the obtained compounds were evaluated and compared with those of AZT and diethyl{(1 0 SR,}methylphosphonate, a saturated phosphonated dihydroisoxazole nucleoside analogue.

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

“…[17][18][19][20][21][22] Following intracellular phosphorylation to their 5 0 -triphosphate forms, they are able to serve as chain terminators, thus 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.…”

1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents

“…There is currently substantial interest in the use of nucleic acids for modifying gene expression for therapeutic purposes. The lipid-conjugated oligonucleotides via 1,3-DC potentiates 90 the cellular uptake of oligonucleotides and allows their intracellular delivery. These non-toxic lipid conjugates 18 ( Figure 4) efficiently inhibit HCV internal ribosome entry site-mediated translation in human hepatic cells.…”

“…These isoxazolines 78, and 79 exhibited lower potency with respect to isoxazolidine derivatives 40, and 41 ( Figure 8). 90 The lesser ability to elicit recognition by the reverse transcriptase, due to the insertion of a double bond in the five-membered heterocycle, can be attributed to a lower 65 molecular flexibility and a lower basicity of the nitrogen atom. Such as it was already mentioned, the bivalent metallic ions assisted the insertion of nucleotides in the growing nucleic acid chain.…”

β-Hydroxyimino Phosphorus Derivatives. An Efficient Tool in Organic Synthesis

“…Recently, phosphonated dihydroisoxazole nucleosides have been prepared via 1,3-dipolar cycloaddition reaction of nitrile oxides with the corresponding vinyl nucleobases for antiviral studies [44]. This synthesis has been performed in a one-step process as shown in Scheme 34.…”