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An AZT Analog with Strongly Pairing Ethynylpyridone Nucleobase and Its Antiviral Activity against HSV1
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2020-12-23 , DOI: 10.1002/cbdv.202000937
Jianyang Han 1 , Christina Funk 2 , Juri Eyberg 1 , Susanne Bailer 2 , Clemens Richert 1
Affiliation  

Challenges resulting from novel viruses or new strains of known viruses call for new antiviral agents. Nucleoside analogs that act as inhibitors of viral polymerases are an attractive class of antivirals. For nucleosides containing thymine, base pairing is weak, making it desirable to identify nucleobase analogs that pair more strongly with adenine, in order to compete successfully with the natural substrate. We have recently described a new class of strongly binding thymidine analogs that contain an ethynylmethylpyridone as base and a C‐nucleosidic linkage to the deoxyribose. Here we report the synthesis of the 3′‐azido‐2′,3′‐deoxyribose derivative of this compound, dubbed AZW, both as free nucleoside and as ProTide phosphoramidate. As a proof of principle, we studied the activity against Herpes simplex virus type 1 (HSV1). Whereas the ProTide phosphoramidate suffered from low solubility, the free nucleoside showed a stronger inhibitory effect than that of AZT in a plaque reduction assay. This suggests that strongly pairing C‐nucleoside analogs of pyrimidines have the potential to become active pharmaceutical ingredients with antiviral activity.

中文翻译:

具有强配对乙炔基吡啶酮核碱基的 AZT 类似物及其对 HSV1 的抗病毒活性

新病毒或已知病毒的新毒株带来的挑战需要新的抗病毒药物。作为病毒聚合酶抑制剂的核苷类似物是一类有吸引力的抗病毒药物。对于含有胸腺嘧啶的核苷,碱基配对较弱,因此需要鉴定与腺嘌呤配对更强的核碱基类似物,以便成功地与天然底物竞争。我们最近描述了一类新的强结合胸苷类似物,它包含一个乙炔基甲基吡啶酮作为碱基和一个与脱氧核糖的 C-核苷键。在这里,我们报告了该化合物的 3'-叠氮基-2',3'-脱氧核糖衍生物的合成,称为 AZW,既作为游离核苷又作为 ProTide 氨基磷酸酯。作为原理证明,我们研究了对单纯疱疹病毒 1 型 (HSV1) 的活性。尽管 ProTide 氨基磷酸酯的溶解度低,但游离核苷在斑块减少试验中显示出比 AZT 更强的抑制作用。这表明嘧啶的强配对 C-核苷类似物有可能成为具有抗病毒活性的药物成分。
更新日期:2020-12-23
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