INTRACELLULAR DELIVERY OF NUCLEOSIDE MONOPHOSPHATES THROUGH A REDUCTASE-MEDIATED ACTIVATION PROCESS

On the basis of three different models (namely: ddU, AZT and PMEA), mo nonucleotide phosphotriester derivatives were designed to be able to l iberate the corresponding monophosphate (or phosphonate) inside the ce ll through a reductase-mediated activation process. Tt was demonstrate d that the use of bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters o f ddUMP (11), AZTMP (12) and PMEA (17) resulted in intracellular deliv ery of the parent monophosphate (or phosphonate). This point was corro borated by observation of an anti-HIV effect of, 11 in various cell li nes, for 12 in CEM TK- cells and by the enhanced activity observed for 17. Furthermore, the reported decomposition data in cell extracts ful ly confirm the validity of this approach and show unambiguously the po tential for intracellular reductase-mediated activation of the startin g drug.