Thiazolo[4,5-d]pyrimidine nucleosides. The synthesis of certain 3-.beta.-D-ribofuranosylthiazolo[4,5-d]pyrimidines as potential immunotherapeutic agents

Abstract

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.

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

“…Guanosine analogs of the thiazolo [4,5-d]pyrimidine ring system, such as 7-thia-8-oxoguanosine, have been reported to possess in vivo activity against a variety of RNA and DNA viruses (17,26,28). Surprisingly, no direct in vitro antiviral activity in virus-infected cells was observed with these compounds (5).…”

“…Several base-modified nucleoside derivatives of the purine analog 5-amino-3-,-D-ribofuranosylthiazolo [4,5-d]pyrimidine-2,7-dione have been synthesized and found to possess antiviral activity in vivo against a variety of RNA and DNA viruses, presumably via stimulation of the host immune system (13,17,27,29). Recently we synthesized a series of derivatives of 5-aminothiazolo [4,5-d]pyrimidine-2,7-dione (7-thia-8-oxoguanine) and assayed them for activity against HCMV in culture (14).…”

A Study of the Efficacy of the Immunomodulatory Compound 7-thia-8-oxoguanosine in Coronavirus 229E Infections in Human Volunteers

“…Experiments on human peripheral blood lymphocytes confirmed the stimulation of NK cells, cytotoxic T cells, the expression of surface antigens, and demonstrated enhanced production of interleukin-1 (Nagahara et al, 1990;Jin et al, 1990;Ojo-Amaize et al, 1991).…”

“…Introduction NARI1 0146, recently described by Nagahara et al (1990), is a nucleoside analogue, 7-thia-8-oxoguanosine and, like a number of other 8-or 7-and 8-substituted guanosines, has been shown to possess immunomodulatory activity (Goodman & Hennen 1986;Wicker et al 1987;Dorsch et aI., 1988;Koo et al, 1988).…”

Activation of anti-hepatitis C virus responses via Toll-like receptor 7

“…Deoxy-Guanosine (dG), deoxy-Cytosine (dC), deoxyAdenosine (dA), and deoxy-Thymidine (dT) and mizoribine were purchased from Sigma. 7-Thia-8-oxo-G (TOG) was synthesized as described (33). R848 [also called resiquimod, 4-amino-2-ethoxymethyl-␣,␣-dimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol] was from GL Synthesis (Worchester, MA).…”