GUANOSINE ANALOGS - SYNTHESIS OF NUCLEOSIDES OF CERTAIN 3-SUBSTITUTED 6-AMINOPYRAZOLO[3,4-D]PYRIMIDIN-4(5H)-ONES AS POTENTIAL IMMUNOTHERAPEUTIC AGENTS

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- l-β-D-ribofuranosyl-pyrazolo[3,4-d]pyrimidin-4(5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-β-D-ribofuranosylpyrazolo[3,4-d]pyri-midin-4(5H)-one, 13b), and the NH2 (3,6-diamino- 1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5/f)-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-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6/f)-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. © 1990, American Chemical Society. All rights reserved.