Our overall objective is to find methods for incorporating CF2 groups into nucleosides, nucleotides, and polynucleotides in order to obtain biologically active molecules. Many of the nucleoside analogs are designed to be inhibitors of DNA synthesis and to block viral replication. Particular emphasis is directed toward analogs with the potential to inhibit HTLV-III encoded reverse transcriptase. With respect to fluorine substituted nucleoside analogs,the objectives are, a) to find ways to replace each of the deoxyribose oxygens by the isosteric, isopolar CF2 group, and b) to replace the 2' CH2 by a CF2 group. Emphasis will be placed on a detailed investigation of the introduction of the CF2 group into carbohydrate analogs via reactions of aldehyde and ketone derivatives. Once it is established, in our current studies on the analogs dApCF2HdA and TpCF2HT, that the O-PO(CF2H)-O linkage between nucleosides is sufficiently stable to nucleases, and if binding to complementary oligonucleotides is significant, then synthesis of sequence specific oligo(deoxyribonucleoside difluoromethylphosphonates) will be pursued. Some new synthetic routes to phosphonate bridged nucleosides will be investigated. 19F NMR studies will be conducted on fluorine containing analogs for which details of binding to enzymes or to complementary oligonucleotides are of interest. New analogs will be provided to other laboratories for testing as antiviral agents and as inhibitors of enzymes involved in DNA biosynthesis (via DNA polymerase or reverse transcriptase). Particular emphasis will be placed on synthesis and testing of potential anti HTLV-III/LAV agents.