Guanosine analogues. 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-1-beta-D-ribofuranosylpyrazolo[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-ribofuranosylpyrazolo[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.
Bontems
R J
RJ
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Anderson
J D
JD
Smee
D F
DF
Jin
A
A
Alaghamandan
H A
HA
Sharma
B S
BS
Jolley
W B
WB
Robins
R K
RK
Cottam
H B
HB
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006151:Guanosine / Q000031:analogs & derivatives*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D012672:Semliki forest virus; D013601:T-Lymphocytes; D014036:Togaviridae Infections / Q000517:prevention & control
D000276:Adjuvants, Immunologic; D011720:Pyrazoles; D011744:Pyrimidinones; D006151:Guanosine