Molecular and Cell Physiology, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstraße 7, D-38124 Braunschweig, Germany.
Eur J Med Chem. 2016 Apr 13;112:164-170. doi: 10.1016/j.ejmech.2016.02.022. Epub 2016 Feb 8.
Tonantzitlolone A, a diterpene isolated from the Mexican plant Stillingia sanguinolenta, shows cytostatic activity. Both the natural product tonantzitlolone A and its synthetic enantiomer induce monoastral spindle formation in cell experiments which indicates inhibitory activity on kinesin-5 mitotic motor molecules. These inhibitory effects on kinesin-5 could be verified in in vitro single-molecule motility assays, where both tonantzitlolones interfered with kinesin-5 binding to its cellular interaction partner microtubules in a concentration-dependent manner, yet with a larger effect of the synthetic enantiomer. In contrast to kinesin-5 inhibition, both tonantzitlolone A enantiomers did not affect conventional kinesin-1 function; hence tonantzitlolones are not unspecific kinesin inhibitors. The observed stronger inhibitory effect of the synthetic enantiomer demonstrates the possibility to enhance the overall moderate anti-proliferative effect of the lead compound tonantzitlolon A by chemical modification.
从墨西哥植物 Stillingia sanguinolenta 中分离得到的二萜类化合物 Tonantzitlolone A 具有细胞抑制活性。天然产物 Tonantzitlolone A 及其合成对映体均在细胞实验中诱导单星纺锤体形成，这表明其对驱动蛋白-5 有抑制活性。在体外单分子运动分析中可以验证对驱动蛋白-5 的抑制作用，其中两种 Tonantzitlolones 均以浓度依赖的方式干扰驱动蛋白-5 与其细胞相互作用伙伴微管的结合，但合成对映体的效果更大。与抑制驱动蛋白-5 相反，Tonantzitlolone A 的两种对映体均不影响传统的驱动蛋白-1 功能；因此，Tonantzitlolones 不是非特异性的驱动蛋白抑制剂。观察到合成对映体的抑制作用更强，表明通过化学修饰有可能增强先导化合物 Tonantzitlolon A 的整体中等抗增殖作用。
