Jin Guangyi, Wu Christina C N, Carson Dennis A, Cottam Howard B
Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0820, USA.
Nucleosides Nucleotides Nucleic Acids. 2006;25(12):1391-7. doi: 10.1080/15257770600918912.
The synthesis of a guanosine analog in the pyrido[2,3-d]pyrimidine ring system has been accomplished by glycosylation of the preformed aromatic heterocyclic base, which was prepared in 2 steps by condensation of methyl acrylate with guanidine carbonate and methyl cyanoacetate in the presence of sodium methoxide, followed by dehydrogenation. The analog was evaluated in vitro for its ability to modulate the innate immune response by acting as an agonist or as an antagonist of Toll-like receptor (TLR) signaling by measuring cytokine induction or inhibition of induction, respectively, in mouse bone marrow-derived macrophages. Despite its structural similarity to 7-thia-8-oxoguanosine, a known TLR7 agonist, the analog was found to antagonize TLR7-induced cytokine induction in this cell-based assay.
通过对预先形成的芳香族杂环碱基进行糖基化反应，已在吡啶并[2,3-d]嘧啶环系统中完成了鸟苷类似物的合成。该芳香族杂环碱基分两步制备，首先在甲醇钠存在下，使丙烯酸甲酯与碳酸胍和氰基乙酸甲酯缩合，然后进行脱氢反应。通过分别测量小鼠骨髓来源巨噬细胞中细胞因子的诱导或诱导抑制情况，在体外评估了该类似物作为Toll样受体（TLR）信号传导的激动剂或拮抗剂来调节先天免疫反应的能力。尽管该类似物在结构上与已知的TLR7激动剂7-硫杂-8-氧代鸟苷相似，但在这种基于细胞的试验中发现它可拮抗TLR7诱导的细胞因子诱导。
