Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents.
Novel analogues of the naturally occurring purine nucleosides were synthesized in the thiazolo[4,5-d]pyrimidine ring system to determine the immunomodulatory effects of insertion of a sulfur atom in place of nitrogen at position 7 of the purine ring. In particular, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7, guanosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H) trione (8, xanthosine analogue), 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (10, inosine analogue), and 7-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidin-2(3H)-one (32, adenosine analogue) were prepared, as well as the 8-mercaptoguanosine (14) and 6-mercaptoguanosine (17) analogues. Single-crystal X-ray studies confirmed the structural assignment of 17 and 32 as having the beta-configuration with the site of glycosylation at N3. The nucleosides were evaluated for their ability to potentiate various murine immune functions in direct comparison to the known active agents 8-bromoguanosine (1), 8-mercaptoguanosine (2), and 7-methyl-8-oxoguanosine (3). Two of the guanosine analogues, 7 and 14, were found to exhibit significant immunoactivity relative to the positive control compounds (1-3), while the adenosine, inosine, xanthosine, and 6-mercaptoguanosine analogues were devoid of activity. Compound 7 exhibited greater immunoactivity than any of the other guanosine analogues and derivatives in all test systems. Specifically, 7 was shown to be about twice as potent as 3 in the murine spleen cell mitogenicity assay. In addition, treatment with 7 produced about a 4-fold increase in natural killer cell cytotoxicity, while treatment with 3 afforded a 3-fold increase over controls. Finally, 7 provided excellent protection (92% survivors compared to 0% for placebo controls) against Semliki Forest virus in mice. Induction of interferon may account for the major mode of action of these guanosine analogues.
Nagahara
K
K
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Anderson
J D
JD
Kini
G D
GD
Dalley
N K
NK
Larson
S B
SB
Smee
D F
DF
Jin
A
A
Sharma
B S
BS
Jolley
W B
WB
Robins
R K
RK
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003602:Cytotoxicity, Immunologic; D004247:DNA / Q000096:biosynthesis; D006151:Guanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007167:Immunotherapy; D007288:Inosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D012672:Semliki forest virus; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014036:Togaviridae Infections / Q000188:drug therapy; D014407:Tumor Cells, Cultured
D011741:Pyrimidine Nucleosides; D012263:Ribonucleosides; D006151:Guanosine; D007288:Inosine; D004247:DNA; D000241:Adenosine