Recently, we demonstrated that ferrocene-containing compounds with a cinchona moiety displayed marked anticancer activity. Here we report on the effects of the most promising isomers encompassing quinine- (compounds 4 and 5) and quinidine-epimers (compounds 6 and 7) – synthesized using improved methods providing controlled diastereoselectivity – in three different human multidrug resistant (MDR) cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87). We observed that the presence of the MDR phenotype did not diminish the activity of the compounds suggesting that ferrocene quinine- and quinidine-epimers are not substrates for P-glycoprotein, which has been indicated as a major mechanism of MDR in the cell lines used. Considering that metal-based anticancer agents mainly act by increasing ROS production, we investigated the potential of ferrocene–quinidine epimers to generate ROS. We found that 6 and 7 more readily increased ROS production and induced mitochondrial damage in MDR cancer cells. According to cell death analysis, 6 and 7 were more active against MDR cancer cells showing collateral sensitivity. In addition, our data suggest that these compounds could act as inhibitors of autophagy. Importantly, simultaneous treatments of 6 and 7 with paclitaxel (PTX) increased the sensitivity of MDR cancer cells to PTX. In conclusion, the ferrocene–quinidine epimers, besides being selective towards MDR cancer cells, could also possess potential to overcome PTX resistance.

中文翻译：

---

具有三唑基-查耳酮连接基的二茂铁-金鸡纳杂种可作为促氧化剂，并使人类癌细胞系对紫杉醇敏感

最近，我们证明了具有金鸡纳部分的含二茂铁化合物显示出显着的抗癌活性。在这里我们报告了最有前途的异构体，包括奎宁-（化合物4和5）和奎尼丁-表异构体（化合物6和7）的作用）-使用改进的方法合成，提供可控的非对映选择性-在三种不同的人类多药耐药（MDR）癌细胞系及其敏感对应物中（非小细胞肺癌NCI-H460 / R / NCI-H460，结直肠癌DLD1-TxR / DLD1和胶质母细胞瘤U87-TxR / U87）。我们观察到MDR表型的存在并不降低化合物的活性，这表明二茂铁奎宁和奎尼丁表位不是P-糖蛋白的底物，这已被证明是所用细胞系中MDR的主要机制。考虑到金属基抗癌剂主要是通过增加ROS产生而起作用，因此我们研究了二茂铁-奎尼丁差向异构体产生ROS的潜力。我们发现6和7更容易增加MDR癌细胞中ROS的产生并诱导线粒体损伤。根据细胞死亡分析，6和7对MDR癌细胞的活性更高，表现出附带敏感性。此外，我们的数据表明这些化合物可以作为自噬的抑制剂。重要的是，紫杉醇（PTX）同时治疗6和7可增加MDR癌细胞对PTX的敏感性。总之，二茂铁-奎尼丁差向异构体除了对MDR癌细胞具有选择性外，还可能具有克服PTX耐药性的潜力。