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

The synthesis and in vitro anti-HIV activity of a novel series of phosphoramidate pronucleotides including a S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protecting group are reported. Such constructs, obtained through different phosphorus chemistries, are characterized by the association of two different anti-HIV nucleoside analogues linked to the phosphorus atom respectively by the sugar residue and the exocyclic amino function of the nucleobase. In vitro, comparative anti-HIV evaluation demonstrates that such original prodrugs are able to allow the efficient intracellular combination release of a 5'-mononucleotide as well as another nucleoside analogue. In human T4-lymphoblastoid cells, the pronucleotide 1 shows remarkable antiviral activity with an EC50 in the nanomolar range (0.6 eta M) and without additional cytotoxicity. In addition, these two pronucleotide models exhibit higher selectivity index than the equimolar mixture of their constitutive nucleoside analogues opening the way to further studies with regard to the current use of drug combinations. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A novel series of phosphoramidate pronucleotides with remarkable anti-HIV activity and efficient intracellular combination release have been reported. These prodrugs exhibit higher selectivity index than the constitutive nucleoside analogues, opening up new possibilities for further drug combination studies.