Aminoferrocene-Based Prodrugs Activated by Reactive Oxygen Species

Abstract

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).

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

“…The phenolate is known to rapidly undergo spontaneous 1,6-elimination with formation of QM that reacts with nucleophilic H 2 O to generate hydroxybenzyl alcohol 20 . We studied the dual stimuli-triggered activation of QCA by investigating NMR spectra after hydrolysis under tumour conditions (Fig.…”

“…We first performed liquid chromatography-mass spectrometry (LC-MS/MS) analysis to confirm the generation of QM and cinnamladehyde in cells. The generation of QM from QCA was indirectly confirmed by measuring the level of cellular GSH, because it is impossible to detect QM that is an intermediate and rapidly reacts with nucleophilic GSH 7,20 . As shown in Supplementary Fig.…”

“…Aryl boronate has been known to rapidly and selectively react with H 2 O 2 to generate QM, which alkylates antioxidant GSH, thus inhibiting the cellular antioxidant systems and triggering cell death 7,20,28,44 . It has been well accepted that the intracellular level of GSH is about o10 mM (refs 20,45,46).…”

“…QM was reported to rapidly alkylate GSH, one of the key antioxidant systems in cells and trigger apoptotic cell death 20 . Hulsman et al 7 reported that the potent anticancer activity of nitric oxide-donating aspirin is attributed to QM, but not nitric oxide.…”

An Environmentally Benign and Cost-Effective Synthesis of Aminoferrocene and Aminoruthenocene

“…To emphasize the importance of such small amino-functionalized ferrocenyl compounds, it has to be reminded that they have already been used, for example, as building blocks for the preparation of ferrocenyl peptide bioconjugates as well as aminoferrocene based prodrugs. [14][15][16][17][18][19][20] One such conjugate showed potential for the electrochemical sensing of chemical warfare agent mimics. [19][20] Over the recent years, such small organometallic constructs have also been used as inserts for parent organic drugs to prepare novel organometallic-based antiparasitic and anticancer drug candidates.…”