Synthesis of 3-hydroxy-2- and -4-pyridone nucleosides as potential antitumor agents

The ribo- and arabinofuranosyl nucleosides of antitumor active 2- and 4-pyridones 1a and 2a were prepared by direct condensation of the silylated bases with either 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4a) or 2,3,5-tri-O-benzyl-1-p-nitrobenzoyl-D-arabinofuranose (7) in the presence of trimethylsilyl triflate (Me3SiOTf). In the case of the arabinofuranosyl nucleosides, separation of the alpha and beta anomers was accomplished at the stage of O-benzyl-protected compounds (8b + 9b, and 10b + 11b) after chemical functionalization of the 3-hydroxy group of the pyridone aglycons with acetyl and benzyl groups, respectively. Deblocking of the protected ribo- and arabinofuranosyl nucleosides was performed by the standard methods. In vitro activity against P-388 cells in culture indicated that the 4-pyridone riboside 6d was the most active member of the series with a twofold lower ID50 than the parent pyridone 2a. However, this and all the other compounds tested in this series showed no activity against the in vivo model system of murine P-388 leukemia at doses ranging from 25 to 400 mg/kg qd 1-5.