Synthesis and anti-HIV evaluation of new 2 ',3 '-dideoxy-3 '-thiacytidine prodrugs

A series of anti-HIV prodrugs possessing various polyaminated side arms hav e been developed. The incorporation of a N-Boc protected monoamine or diami ne side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-1 89) provided an increase in antiviral potency, which could be several order s magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodr ugs which differ from each other by the length, the nature of the 5'-O func tion and the 5'-O or /and N-4 position on the nucleoside moiety were synthe sized. Among this new series of prodrugs, several congeners (12c and 12a) w ere found to inhibit HIV-1 replication in cell culture with 50% effective c oncentrations EC50 of 10 and 50 nM respectively,in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentrat ion of 0.01 nM. The synthesis and the antiviral properties of these compoun ds are discussed.