Li Gen, Zhao Jiang-Yu, Niu Chao, Nie Li-Fei, Dong Chang-Zhi, Aisa Haji Akber
The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France.
The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1484-1487. doi: 10.1016/j.bmcl.2016.06.011. Epub 2016 Jun 6.
A series of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters were synthesized via the condensation of methyl rupestonate with various aldehydes in the presence of LDA. This mixed aldol reaction was highly stereoselective and all the new compounds were elucidated by detailed NMR and MS analyses. The absolute configurations of the newly formed stereocenters were further confirmed by X-ray crystallographic analysis of 3d, the results of which were found to be opposite to the prediction based on Zimmerman-Traxler's and Houk's models. All the compounds synthesized were then evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and B viruses. The data showed that 3p displayed the highest activity against influenza A H1N1 (IC=0.69μg/mL) and H3N2 (IC=0.69μg/mL) viruses, which were even better than Ribavirin and Oseltmivir. On the other hand, both 3c and 3o were found to show comparable activities with the reference drugs in inhibiting both influenza A and B viruses. Further studies will focus on reducing the cytotoxicity of the hits reported in this work.
通过在LDA存在下使鲁佩斯通酸甲酯与各种醛缩合，合成了一系列1-(1'-羟烷基)鲁佩斯通酸甲酯。这种混合羟醛反应具有高度的立体选择性，所有新化合物都通过详细的核磁共振和质谱分析进行了表征。通过对3d进行X射线晶体学分析进一步确定了新形成的立体中心的绝对构型，结果发现其与基于齐默尔曼-特拉克斯勒模型和霍克模型的预测相反。然后对所有合成的化合物进行了抗甲型流感病毒（H1N1和H3N2）和乙型流感病毒的体外抑制活性评估。数据表明，3p对甲型流感病毒H1N1（IC = 0.69μg/mL）和H3N2（IC = 0.69μg/mL）显示出最高活性，甚至优于利巴韦林和奥司他韦。另一方面，发现3c和3o在抑制甲型和乙型流感病毒方面与参考药物具有相当的活性。进一步的研究将集中于降低本研究中报道的活性化合物的细胞毒性。
