Novel Phosphonate Nucleotide Analogs as Anti-HIV Agents

Our objective is to discover new anti-HIV agents or lead compounds which may be developed into clinthis Phase I program, our research interest will focus on the design and synthesis of novel fluorinanucleotide analogues which would isosterically and isoelectronically mimic the monophosphates of fouand clinically used anti-HIV drugs, i.e., AZT, ddC, ddI, and d4T. These synthesized compounds will bvitro antiviral activity against HIV and other DNA viruses. It is assumed that such selected fluorinphosphonate nucleotides would not only bring the second dissociation constant, pKa2, closer to thosephosphate monoesters and would help the modified nucleotides to bypass the first enzymatic phosphoryactivation process. Such fluorine substitution would introduce a certain degree of rigidity to "freeribofuranose ring in the "active" conformation which is capable of binding effectively to HIV revers