前药
化学
活性氧
催化作用
谷胱甘肽
癌细胞
激进的
生物化学
烷基化
羟基自由基
反应中间体
组合化学
癌症
酶
医学
内科学
作者
Helen Hagen,Paul Marzenell,Elmar Jentzsch,Frederik Wenz,Marlon R. Veldwijk,Andriy Mokhir
摘要
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).
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