Phosphonylmethyl Ethers of Nucleosides and Their Acyclic Analogues

Structure-activity investigation in the series of acyclic nucleotide analogs bearing a modified phosphoric acid residue at the side-chain revealed two novel classes of antivirals: N--(3-hydroxy-2-phosphonylmethoxypropyl)- (HPMP-) and N-(2-phosphonylmethoxyethyl) (PME-) derivatives of heterocyclic bases. Adenine, guanine, 2-aminoadenine and (in the HPMP-series) cytosine derivatives act specifically against DNA viruses (herpes viruses,adenoviruses,poxviruses). The PME-compounds are also active against retroviruses (MSV,HIV)and exhibit a cytostatic effect on L-1210 mouse leukemia cells.The drugs are converted by the action of cellular nucleotide kinases into their diphosphates and inhibit viral and, to a lesser extent, cellular DNA synthesis. These metabolites exert a comparatively low inhibitory effect on viral (HSV-1) DNA polymerase. The diphosphates derived from PME-compounds strongly inhibit viral (HSV-1) ribonucleotide reductase and AMV reverse transcriptase.