Synthesis and Biological Activity of Isopolar Acyclic Nucleotide Analogs

Abstract

This chapter summarizes the results of the vast effort in the field of acyclic nucleoside phosphonates (ANPs). A novel type of nucleotide analogs, nucleoside O-phosphonomethyl ethers were sysnthesized, which are isopolar with nucleotides and whose sp3-hybridized CH2 grouping should warrant the conformational adaptability of nucleotide molecules. Pilot studies demonstrated that the 5'-O-phosphonomethyl ribonucleosides inhibit some nucleotidases and that the triphosphate analogs of GTP and ATP containing a modified or phosphorus atom can serve as phosphate donors in uridine kinase catalyzed reactions, whereas the analogs of UTP and/or CTP inhibit this process. It was also demonstrated that such ATP or CTP analogs inhibit DNA-dependent RNA polymerase catalyzed RNA synthesis, but can be incorporated into the growing RNA chain. Despite these significant in vitro activities, neither the 5'-O-phosphonomethyl ethers of natural ribonucleosides, nor analogous compounds derived from biologically active (e.g., antiviral or cytostatic) nucleosides exhibited any significant cytostatic or antiviral properties in vitro. However, potent antiviral activity of HPMPA, a structurally related molecule bearing the phosphonomethyl ether group linked to the side-chain of the acyclic adenosine analog DHPA [9-(2,3-dihydroxypropyl)adenine] was discovered. However, while the parent metabolically inert adenosine analog inhibits RNA viruses by virtue of interfering with cap-methylation of viral mRNA (via inhibition of SAH hydrolase, the activity of its new phosphonate derivative was directed specifically against DNA viruses. The regio- and enantiospecific syntheses proved that the antiviral activity is linked to the 2'-(S)-isomer only.