SYNTHESIS AND ANTIVIRAL ACTIVITY OF PYRANOSYLPHOSPHONIC ACID NUCLEOTIDE ANALOGS

Pyranosyl nucleotide analogues have been designed so that the intramol ecular base to phosphorus distance closely approximates that of natura l. nucleotides. This was achieved by attaching the phosphorus directly at the anomeric position and the base at the 4-position of the carboh ydrate. A series of compounds incorporating natural bases and having t his novel structure were made via a short synthesis starting from comm ercially available glycals. Addition of triisopropyl phosphite to the glycals furnished alpha- and beta-2-enopyranosylphosphonates which wer e then substituted with the heterocycle using Mitsunobu chemistry. Dep rotection afforded the 2',3'-unsaturated isonucleotide analogue. In so me cases the deprotection sequence induced double-bond migration leadi ng to the 1',2'-unsaturated derivative. NMR spectroscopic structural a nalysis established an axial preference for the base and an equatorial preference for the beta-phosphorus which results in intramolecular ba se to phosphorus distances within 1 Angstrom of that of natural nucleo tides. All of the deprotected compounds were screened for inhibition o f HCMV, HSV-2, and HIV replication. Several compounds inhibited HCMV a nd HSV-2, the most potent of which was the unsaturated cytosine analog ue 18 (HCMV IC50 = 10 mu M, HSV-2 IC50 = 85 mu M). None of the compoun ds were cytotoxic at the highest dose (1 mM) tested. None of the compo unds were inhibitory to HIV.