A novel immunopotentiating agent, 5-amino-3-0i-D-ribofuranosylthiazolo [4,5-d]pyrimidine-2,7(3H,6H)-dione (7-thia-8-oxoguanosine), lacks virus-inhibitory properties in vitro but induces interferon and potentiates immune functions, such as natural killer cell activity. It was evaluated in rodent models to determine the spectrum of antiviral activity and effective treatment regimens. At cells (4, 21), natural killer cells, and macrophages (8). They also induce interferon (8).Another related compound, 7-methyl-8-oxoguanosine, is also reported to be a B-cell activator (6). The apparent molecular configurations that are important for this activity reside in the pyrimidine portion of the molecule (to resemble guanosine) and in the substitutions at the 7 and 8 positions. Adenosine-or inosinelike structures (related to the above compounds) do not appear to be immunopotentiators. Another series of heterocyclic compounds, phenyl-substituted pyrimidinones possessing a guaninelike functionality, can activate B cells (20) and natural killer cells (12), induce interferon (15), and exhibit antiviral activity in vivo (1,15,22). The most studied of these compounds is referred to as ABPP or bropirimine.The modes of action of these guanine and guanosine analogs are the subject of ongoing research. Wicker et al. (20) have suggested the role of a biochemical pathway common to several immune cell types in immune cell activation. Research performed in our laboratory strongly implicates guanine nucleotide (G) binding proteins of the phosphatidylinositol-protein kinase C pathway as the site of action of these compounds

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C-Glycosylation of two guanine analogues, 9-deaza- and 7-deazaguanine, has been achieved under Friedel-Crafts conditions, providing a direct synthetic route to 9-deazaguanosine (4; 2-amino-7-beta-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one) and 8-beta-D-ribofuranosyl-7-deazaguanine (16), respectively. This electrophilic C-glycosylation was applied successfully to six guanine and substituted-guanine analogues resulting in yields of approximately 50%. This represents the first reported C-ribosylation of preformed nitrogen heterocycles isosteric with guanine. These C-nucleosides were evaluated for their ability to provide protection against a lethal Semliki Forest virus infection in mice, relative to 7-thia-8-oxoguanosine which was used as a positive control. Two of the C-nucleosides, 2-amino-6-chloro-5-methyl-7-beta-D-ribofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (12) and the corresponding 6-bromo derivative (13), showed good prophylactic activity in this virus model system.

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The nucleotide analog 7-deazaguanosine has not previously been reported to possess biological (antiviral or antitumor) properties in cell culture or in vivo. Up to 10(5) U of interferon per ml was detected in mouse sera 1 to 4 h following oral (200-mg/kg of body weight) and intraperitoneal (50-mg/kg) doses of the compound. 7-Deazaguanosine also caused significant activation of natural killer and phagocytic cells but did not augment T- and B-cell blastogenesis. Intraperitoneal treatments of 50, 100, and 200 mg/kg/day administered 24 and 18 h before virus inoculation were highly protective in mice inoculated with lethal doses of Semliki Forest or San Angelo viruses. Less but still significant survivor increases were evident in treated mice infected with banzi or encephalomyocarditis viruses. In most cases, the degree of antiviral activity was similar to that exhibited by the biological response modifier 7-thia-8-oxoguanosine. 7-Thia-8-oxoguanosine was more potent than 7-deazaguanosine against encephalomyocarditis virus in mice, however. Oral efficacy was achieved with 7-deazaguanosine treatments of greater than or equal to 100 mg/kg against all virus infections, whereas 7-thia-8-oxoguanosine is reported to be devoid of oral activity in rodents. Thus, 7-deazaguanosine represents the first reported orally active nucleoside biological response modifier exhibiting broad-spectrum antiviral activity against particular types of RNA viruses.