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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and cytotoxicity of 4-amino-5-oxopyrido2,3-dpyrimidine nucleosides
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Synthesis and cytotoxicity of 4-amino-5-oxopyrido2,3-dpyrimidine nucleosides

机译：4-氨基-5-氧代吡啶并2,3-d嘧啶核苷的合成及细胞毒性

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A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido2,3-dpyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido2,3-dpyrimidine. A variety of 1-0-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido2,3-dpyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyridol2,3-dpyrimidine nucleosides. Further derivatizations provided an additional group of pyrido2,3-dpyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido-2,3-dpyrimidine (Ib) being the most potent proliferation inhibitor (EC50: 0.06-0.08 mu M) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC50: 0.73 mu M) and has a favorable in vitro selectivity index (28). References: 29
机译：许多核苷类似物已在临床上用作抗癌药物或在临床研究中进行评估，而新的核苷类似物继续显示出前景。在本文中，我们报道了一系列新的吡啶并[2,3-d]嘧啶核苷的合成和细胞毒性。分两步将2-氨基-3-氰基-4-甲氧基吡啶转化为4-氨基-5-氧代吡啶并[2,3-d]嘧啶。将多种1-0乙酰化戊糖衍生物与硅烷化4-氨基-5-氧代吡啶并[2,3-d]嘧啶缩合，然后进行保护，得到一系列4-氨基-5-氧代吡喃醇[2,3-d]嘧啶核苷。进一步的衍生化提供了一组额外的吡啶并[2,3-d]嘧啶核苷。评估了这些核苷对人类前列腺癌 （HTB-81） 和小鼠黑色素瘤 （B16） 细胞以及正常人成纤维细胞 （NHF） 的体外细胞毒性。许多化合物（1a，b，2a-c，f，3f + 4d）对癌细胞显示出显着的细胞毒性，其中4-氨基-5-氧代-8-（β-D-呋喃核糖基）吡啶-[2,3-d]嘧啶（Ib）是所有测试类型细胞最有效的增殖抑制剂（EC50：0.06-0.08μM）。然而，观察到 4-氨基-5-氧代-8-（β-D-呋喃木糖基）嘧啶 （2b） 对癌细胞有选择性抑制作用，它是 HTB-81 的有效抑制剂 （EC50： 0.73 μ M），具有良好的体外选择性指数 （28）。[参考文献： 29]

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