An original pronucleotide strategy for the simultaneous delivery of two bioactive drugs

The synthesis and in vitro anti-HIV activity of a novel series phosphoramidate pronucleotides including S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protecting are reported. Such constructs, obtained through different phosphorus chemistries, characterized by the association two nucleoside analogues linked to atom respectively sugar residue exocyclic amino function nucleobase. In vitro, comparative evaluation demonstrates that such original prodrugs able allow efficient intracellular combination release 5′-mononucleotide well another analogue. human T4-lymphoblastoid cells, pronucleotide 1 shows remarkable antiviral with an EC50 nanomolar range (0.6 ηM) without additional cytotoxicity. addition, these models exhibit higher selectivity index than equimolar mixture their constitutive opening way further studies regard current use drug combinations.