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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).

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Hagen H,Marzenell P,Jentzsch E,Wenz F,Veldwijk MR,Mokhir A

doi

10.1021/jm2014937

subject

Has Abstract

pub_date

2012-01-26 00:00:00

pages

924-34

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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