DECOMPOSITION PATHWAYS AND IN-VITRO HIV INHIBITORY EFFECTS OF ISODDA PRONUCLEOTIDES - TOWARD A RATIONAL APPROACH FOR INTRACELLULAR DELIVERYOF NUCLEOSIDE 5'-MONOPHOSPHATES

The decomposition pathways and kinetics in various biological media an d the in vitro anti-HIV-1 and anti-HIV-2 activities of four derivative s of the 5'-mononucleotide of isoddA incorporating carboxylate esteras e-labile transient phosphate protecting groups are reported and compar ed: namely, two mononucleoside aryl phosphoramidate derivatives 1a,b a nd two mononucleoside phosphotriester derivatives incorporating two S- acyl-2-thioethyl groups 2a,b. All four compounds show better antiviral activity, compared to the parent nucleoside analog isoddA. The result s highlight that both types of compounds act as pronucleotides, i.e. t hey exert their antiviral effect via intracellular delivery of the 5'- mononucleotide of isoddA. The results may give insights for the design of new more efficient pronucleotides.