DESIGN, SYNTHESIS, AND STRUCTURE-ACTIVITY RELATIONSHIP OF NOVEL DINUCLEOTIDE ANALOGS AS AGENTS AGAINST HERPES AND HUMAN IMMUNODEFICIENCY VIRUSES

A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosa l adenosine deaminase. This inhibitory property allows it to exert gre at synergistic effect on certain antiviral agents (e.g., ara-A, 37). P hosphonate 13 was not phosphorylated by the bovine brain guanylate kin ase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of b iologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity agai nst herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucl eoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respect ive phosphonoamidates 53-56 were also synthesized as new compounds, am ong which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bea ring a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degrada tion by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen en zymes.