David R. Borcherding

Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α

Murine macrophage-derived tumor necrosis factor alpha (TNF-alpha) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-kappa B (NF-kappa B) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominantly express the adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A3 receptor, blocked the endotoxin induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A3 receptor antagonist BW-1433 dose-dependently reversed this adenosine inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A3 receptor interrupts the endotoxin CD14 receptor signal transduction pathway and blocks induction of cytokine TNF-alpha, revealing a novel cross-talk between the murine adenosine A3 receptor and the endotoxin CD14 receptor in J774.1 macrophages.

9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine and -3-deazaadenine: analogs of neplanocin A which retain potent antiviral activity but exhibit reduced cytotoxicity.

Two synthetic analogs of neplanocin A, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase, were found in this study to inhibit vaccinia virus replication in murine L929 cells but to have reduced cytotoxicity compared with that of the parent compound. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of neplanocin A and that transformation by cellular adenosine kinase mediates its cytotoxic properties.

A 9-step enantiospecific synthesis of (−)-aristeromycin from D-ribonic acid γ-lactone

Abstract A short, efficient, enantiospecific total synthesis of (-)-aristeromycin, which can be modified for making analogues of this carbocyclic nucleoside, is reported.

(1′R, 2′S, 3′R)-9-(2′, 3′-Dihydroxycyclopentan-1′-yl)-Adenine and −3-Deaza-Adenine: Analogues of Aristeromycin Which Exhibit Potent Antiviral Activity with Reduced Cytotoxicity

Two synthetic analogues of aristeromycin, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase and adenosine deaminase, were found in this study to inhibit vaccinia virus replication in murine L929 cells and to have reduced cytotoxicity compared with that of the parent compound. Aristeromycin was shown to produce cytocidal effects on murine L929 cells, whereas the synthetic analogues produced cytostatic effects on cell growth. The antiviral effects of these synthetic analogues are correlated with their ability to elevate the intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of aristeromycin and that transformation of aristeromycin by cellular adenosine kinase mediates its cytocidal properties.

The synthesis and biological activity of a highly selective adenosine A2a receptor agonist.

Three novel nucleosides 1, 2, and 3 were prepared that contained side chains at the 2-position of adenosine. Compound 1 was shown to be the most selective A2a receptor agonist reported to date having an A1/A2 ratio of 2400. In addition, compound 1 was shown to reduce blood pressure in rats and dogs with only minimal effects on heart rate.