title: 4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions.
abstract: Aminoferrocene-based prodrugs are activated in the presence of cancer-specific amounts of reactive oxygen species, e.g. H2O2, with the formation of products of two types: Fe-containing complexes, which catalyze generation of HO and O2(-), and quinone methides, which alkylate glutathione and inhibit the antioxidative system of the cell. Both processes act synergistically by increasing the oxidative stress in cancer cells thereby leading to their death. However, in the activation step including the cleavage of a B-C bond one molecule of H2O2 is consumed that counteracts the desired effect of the products released from aminoferrocenes. We replaced an H2O2-sensitive trigger in original prodrugs with an azide group. This trigger is slowly reduced in the presence of glutathione with the formation of an unstable arylamine intermediate, which decomposes with the release of iron ions and iminoquinone methides. These products induce strong oxidative stress in cells as we confirmed using 2',7'-dichlorodihydrofluorescin diacetate reagent in combination with flow cytometry. In this case the activation process does not consume H2O2. Correspondingly, we observed that the azide-containing prodrug is substantially more toxic towards human promyelocytic leukemia cell line HL-60 (IC50=27±4μM) than its H2O2-responsive analogue (IC50>50μM).
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Kinski
authors.affiliation: Ruprecht-Karls-University of Heidelberg, Institute of Inorganic Chemistry, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Marzenell
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Hofer
authors.affiliation: Ruprecht-Karls-University of Heidelberg, Institute of Inorganic Chemistry, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Hagen
authors.affiliation: University of California, Santa Cruz, School of Chemistry and Biochemistry, 1156 High Street, Santa Cruz, CA 95064, USA.
authors.forename: Jevgenij A
authors.initials: JA
authors.lastname: Raskatov
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Faculty of Medicine, Department of Medicine IV, Translational Research Center (TRC), Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Karl X
authors.initials: KX
authors.lastname: Knaup
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Inorganic and General Chemistry II, Egerlandstr. 1, 91058 Erlangen, Germany.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Zolnhofer
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Inorganic and General Chemistry II, Egerlandstr. 1, 91058 Erlangen, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany. Electronic address: Andriy.Mokhir@fau.de.
authors.forename: Andriy
authors.initials: A
authors.lastname: Mokhir
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005296:Ferrous Compounds / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000378:metabolism; D045563:Indolequinones / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D000075163:Metallocenes; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D005296:Ferrous Compounds; D045563:Indolequinones; D000075163:Metallocenes; D011355:Prodrugs; D011809:Quinones; C116897:iminoquinone; C068040:quinone methide; C014747:phenylazide; C078996:ferrocene carbamate; D006861:Hydrogen Peroxide; D007501:Iron; D005978:Glutathione
keywords: Azide; Cancer; Ferrocene; Prodrug; Reduction