Guanosine analogs. Synthesis of nucleosides of certain 3-substituted 6-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones as potential immunotherapeutic agents

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Abstract
Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-.beta.-D-ribofuranosylpyrazolol[3,4-d]pyrimidin-4(5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one, 13b), and the NH2 (3,6-diamino-1-.beta.-D-ribofuranosylpyrazolol[3,4-d]pyrimidin-4(5H)-one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-.beta.-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.

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