Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents
| Autor: | K Nagahara, Ganesh D. Kini, Brahma S. Sharma, Roland K. Robins, Jack D. Anderson, Steven B. Larson, N. K. Dalley, Donald F. Smee, Weldon B. Jolley, Ai Jin |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Purine
Cytotoxicity Immunologic Adenosine Pyrimidine Chemical Phenomena Lymphoma Stereochemistry T-Lymphocytes Guanosine chemistry.chemical_compound Mice Togaviridae Infections Drug Discovery medicine Tumor Cells Cultured Animals Inosine Bicyclic molecule Molecular Structure Biological activity Xanthosine DNA Pyrimidine Nucleosides Semliki forest virus Killer Cells Natural Chemistry chemistry Molecular Medicine Immunotherapy Ribonucleosides Cell Division Spleen medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 33(1) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|