Solid-phase synthesis of 5′-O-β,γ-methylenetriphosphate derivatives of nucleosides and evaluation of their inhibitory activity against HIV-1 reverse transcriptase

Bis(dichlorophosphino)methane was converted to a β,γ-methylenetriphosphitylating reagent. The reagent was immobilized on aminomethyl polystyrene resin-bound linker of 4-acetoxy-3-phenylbenzyl alcohol to afford a polymer-bound β,γ-methylenetriphosphitylating reagent, which was reacted with unprotected nucleosides followed by oxidation with tert-butyl hydroperoxide, deprotection of cyanoethoxy groups with DBU, and acidic cleavage to produce 5′-O-β,γ-methylene triphosphate nucleosides in 53-82% overall yields. Among all the compounds, cytidine 5′-O-β,γ-methylenetriphosphate inhibited completely RNase H activity of HIV-1 reverse transcriptase at 700 μM.

Graphical abstractMethods for the synthesis of 5′-O-β,γ-methylenetriphosphate derivatives of nucleosides are described.Download full-size image