title: 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).
authors.affiliation: Institute of Inorganic Chemistry, Ruprecht-Karls-University of Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Hagen
authors.forename: Paul
authors.initials: P
authors.lastname: Marzenell
authors.forename: Elmar
authors.initials: E
authors.lastname: Jentzsch
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Veldwijk
authors.forename: Andriy
authors.initials: A
authors.lastname: Mokhir
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical / Q000378:metabolism; D045563:Indolequinones / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D000075163:Metallocenes; D018384:Oxidative Stress; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D056831:Coordination Complexes; D005296:Ferrous Compounds; D045563:Indolequinones; D061965:Matrix Metalloproteinase Inhibitors; D000075163:Metallocenes; D011355:Prodrugs; D017382:Reactive Oxygen Species; C068040:quinone methide; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron; C004998:ferrocene