Aryl nucleoside H-phosphonates. Part 16: Synthesis and anti-HIV-1 activity of di-aryl nucleoside phosphotriesters

Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5′-monophosphates, and their efficiency correlated well with the pKa values of the aryloxy groups present.

Various phosphotriesters, produced in a ‘one-pot’ approach from nucleosid-5′-yl H-phosphonates and phenols, exhibited significant anti HIV-1 activity, and were found to act, at least partially, as true pronucleotides.Figure optionsDownload as PowerPoint slide