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In order to evaluate their antiviral properties, a series of 4'-C-methyl-beta-D-ribofuranosyl purine and pyrimidine nucleosides has been prepared. Unfortunately, none of these 4'-branched nucleosides showed any antiviral activity or cytotoxcity when tested against HIV, HBV, and Yellow Fever virus.

A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl]]methylphosphonate (9), followed by deesterification reaction in the presence of TMSBr. In similar way, PMAMA, PMAMC, and PMAMT were prepared.

A unique series of simple unnatural L-nucleosides that specifically inhibit hepatitis B virus (HBV) replication has been discovered. These molecules have in common a hydroxyl group in the 3'-position (3'-OH) of the beta-L-2'-deoxyribose sugar that confers antiviral activity specifically against hepadnaviruses. Replacement of the 3'-OH broadens activity to other viruses. Substitution in the base decreases antiviral potency and selectivity. Human DNA polymerases and mitochondrial function are not effected. Plasma viremia is reduced up to 8 logs in a woodchuck model of chronic HBV infection. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.

Exposure to 10 &M L-FddCMP-bisSATE led to formation of intracellular L-FddCTP levels of 410.1(+/-) +/- 46.2 and 242.1 +/- 13.2 pmol/10(6) cells in unstimulated and PHAstimulated PBM cells, respectively; whereas, exposure of cells to the parent nucleoside, L-FddC, generated 5-10-fold less L-FddCTP. In Hep-G2 cells and EGF/HGF stimulated and unstimulated primary cultured hepatocytes, the active metabolite reached 113 +/- 29, 23.9 +/- 15.6, and 20.6 +/- 10.5 pmol/10(6) cells. Three other metabolites, L-FddCMP-monoSATE, L-FddCMP-SH, and M I, were detected intracellularly and extracellularly in all cell types examined. Intravenous administered dose of 3 mg/kg L-FddCMP-bisSATE to rhesus monkeys resulted in plasma concentration levels of 2.06 +/- 1.00 and 0.39 +/- 0.15 &M of L-FddCMP-monoSATE and L-FddC, respectively, while the prodrug was completely cleared metabolically within 15 min. Following oral administration of an equivalent dose, the absolute oral bioavailability of L-FddC derived from L-FddCMP-bisSATE administration was 65%.