Institute of Inorganic Chemistry, Ruprecht-Karls-University of Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
J Med Chem. 2012 Jan 26;55(2):924-34. doi: 10.1021/jm2014937. Epub 2012 Jan 11.
Cancer cells generally generate higher amounts of reactive oxygen species than normal cells. On the basis of this difference, prodrugs have been developed (e.g., hydroxyferrocifen), which remain inactive in normal cells, but become activated in cancer cells. In this work we describe novel aminoferrocene-based prodrugs, which, in contrast to hydroxyferrocifen, after activation form not only quinone methides (QMs), but also catalysts (iron or ferrocenium ions). The released products act in a concerted fashion. In particular, QMs alkylate glutathione, thereby inhibiting the antioxidative system of the cell, whereas the iron species induce catalytic generation of hydroxyl radicals. Since the catalysts are formed as products of the activation reaction, it proceeds autocatalytically. The most potent prodrug described here is toxic toward cancer cells (human promyelocytic leukemia (HL-60), IC(50) = 9 μM, and human glioblastoma-astrocytoma (U373), IC(50) = 25 μM), but not toxic (up to 100 μM) toward representative nonmalignant cells (fibroblasts).
癌细胞通常比正常细胞产生更多的活性氧物种。基于这一差异，已经开发出前药（例如羟基ferrocifen），它们在正常细胞中保持不活跃，但在癌细胞中被激活。在这项工作中，我们描述了新型的基于氨基酸ferrocene 的前药，与羟基ferrocifen 不同，这些前药在激活后不仅形成醌甲基化物（QMs），还形成催化剂（铁或 ferrocenium 离子）。释放的产物协同作用。特别地，QMs 烷化谷胱甘肽，从而抑制细胞的抗氧化系统，而铁物种诱导羟基自由基的催化生成。由于催化剂是作为激活反应的产物形成的，因此它会自动催化。这里描述的最有效的前药对癌细胞（人早幼粒细胞白血病（HL-60），IC（50）= 9 μM，和人胶质母细胞瘤-星形细胞瘤（U373），IC（50）= 25 μM）有毒，但对代表性的非恶性细胞（成纤维细胞）无毒（高达 100 μM）。
