4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions

Kinski E, Marzenell P, Hofer W, Hagen H, Raskatov JA, Knaup K, Zolnhofer E, Meyer K, Mokhir A (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Journal of Inorganic Biochemistry Elsevier

Book Volume: 160

Pages Range: 218-224

DOI: 10.1016/j.jinorgbio.2016.02.023

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 ± 4 μM) than its H2O2-responsive analogue (IC50 > 50 μM).

Authors with CRIS profile

Walter Hofer Lehrstuhl für Organische Chemie II Karl Knaup Department of Medicine 4 – Nephrology and Hypertension Eva Zolnhofer Lehrstuhl für Anorganische und Allgemeine Chemie Karsten Meyer Lehrstuhl für Anorganische und Allgemeine Chemie Andriy Mokhir Professur für Organische Chemie

Involved external institutions

Ruprecht-Karls-Universität Heidelberg DE Germany (DE) University of California Santa Cruz US United States (USA) (US)

How to cite

APA:

Kinski, E., Marzenell, P., Hofer, W., Hagen, H., Raskatov, J.A., Knaup, K.,... Mokhir, A. (2016). 4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions. Journal of Inorganic Biochemistry, 160, 218-224. https://dx.doi.org/10.1016/j.jinorgbio.2016.02.023

MLA:

Kinski, Elisa, et al. "4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions." Journal of Inorganic Biochemistry 160 (2016): 218-224.

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