Synthesis of C-4′Truncated Phosphonated Carbocyclic 2′-Oxa-3′-azanucleosides as Antiviral Agents

Abstract

A new template of C-4'-truncated phosphonated nucleosides (TPCOANs) has been obtained in good yields according to two different routes which exploit the reactivity of a phosphonated nitrone. The one-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl nucleobases leads to the unnatural alpha-nucleosides as the main adducts. On the other hand, the target beta-anomers have been obtained in high yield by a two-step procedure based on the 1,3-dipolar cycloaddition of a phosphonated nitrone with vinyl acetate followed by nucleosidation reaction. The reactivity of the phosphonated nitrone has been investigated trough quantum mechanical DFT calculations at the B3LYP/D95+(d,p) theory level. Preliminary biological assays show that beta-anomers of TPCOANs are able to inhibit the reverse transcriptase of different retroviruses at concentrations in the nanomolar range, with a potency comparable with that of tenofovir.

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.…”

“…In this context, we have recently reported the synthesis of phosphonated carbocyclic 2 0 -oxa-3 0 -azanucleosides (PCOANS) 5, which have shown to be potent inhibitors of RT of different retroviruses 21 ( Fig. 2).…”

5-(3-Phosphonated 1H-1,2,3-triazol-4-yl)isoxazolidines: synthesis, DFT studies and biological properties

“…In particular, the 1 The observed stereochemistry is in deep contrast with the precedent results reported for the cycloaddition reactions of this nitrone with various electron-rich, electron-poor and conjugative dipolarophiles, in which the trans adducts are the major stereoisomers. 8,30 Then, to rationalize the observed high regio-and stereoselectivity, a computational study at DFT level [31][32][33][34] was performed using the M062X/6-31G(d,p) calculations.…”

“…[5][6] In particular, N,O-nucleosides, characterized by the presence of an isoxazolidine system as mimetic of the ribose spacer, have been designed and shown to be endowed with antiviral and/or antitumoral activity. [7][8][9][10][11][12][13] PCOANS 1 have shown to be potent inhibitors of reverse trascriptase (RT) of different retroviruses; [14][15][16][17] Structural modifications concerning the purine or pyrimidine nucleobases have also been investigated [19][20] and shown to led to biologically interesting compounds. In particular, the use of unnatural heterocycles as nucleobases in the design of novel nucleoside analogues not only enhances the in vivo stability of the obtained compounds, but also confers novel mechanisms of action.…”

(Z)-1-(1,3-Diphenyl-1H-pyrazol-4-yl)-N-phenylmethanimineN-oxide

“…Nitrones have various uses including as spin-trap reagents (Villamena et al, 2007) and therapeutic agents (Piperno et al, 2010). They react in [3 + 2] dipolar cycloadditions with carious dipolarophiles to construct functionalized isoxazolidines, which are useful intermediates in organic synthesis (Dell, 1998).…”