Institute of Organic Chemistry, University of Stuttgart, DE-70569, Stuttgart, Germany.
Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, DE-70569, Stuttgart, Germany.
Chem Biodivers. 2021 Jan;18(1):e2000937. doi: 10.1002/cbdv.202000937. Epub 2020 Dec 23.
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.
新型病毒或已知病毒的新菌株所带来的挑战需要新的抗病毒药物。核苷类似物作为病毒聚合酶的抑制剂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，因此需要确定与腺嘌呤结合更强的核苷类似物，以成功与天然底物竞争。我们最近描述了一类新的结合紧密的胸苷类似物，它们含有作为碱基的乙炔基甲基吡啶酮和与脱氧核糖的 C-核苷键。在这里，我们报告了该化合物的 3'-叠氮-2',3'-脱氧核糖衍生物，称为 AZW，既作为游离核苷，也作为 ProTide 磷酰胺。作为原理的证明，我们研究了其对单纯疱疹病毒 1（HSV1）的活性。虽然 ProTide 磷酰胺的溶解度较低，但在蚀斑减少测定中，游离核苷的抑制作用强于 AZT。这表明具有强配对的嘧啶 C-核苷类似物有可能成为具有抗病毒活性的活性药物成分。
