title: Induction of Cytotoxicity through Photorelease of Aminoferrocene.
abstract: Reactive oxygen species (ROS)-activated aminoferrocene-based anticancer prodrug candidates successfully take advantage of intrinsically high amounts of ROS in tumor tissues. Interestingly, the ROS-initiated activation of these prodrug candidates leads to formation of unstable aminoferrocene (Fc-NH2) derivatives, which decay to iron ions. The latter catalytically increases ROS concentration to a lethal level. In this work, we prepared light-controlled aminoferrocene prodrug candidates by derivatizing Fc-NH2 with an o-nitrophenyl and an o-nitrobiphenyl photolabile protecting group (PLPG), respectively, and by further conjugation to a mitochondria localization signal (MLS) peptide (Cys-D-Arg-Phe-Lys-NH2). The resulting bioconjugates were found to be more stable and less cytotoxic, in the dark, toward human promyelocytic leukemia cells (HL-60) compared to Fc-NH2. Upon light irradiation at 355 nm, both conjugates released Fc-NH2, albeit with very different photolysis quantum yields. The o-nitrobiphenyl photocage was in fact several orders of magnitude more efficient than the o-nitrophenyl photocage in releasing Fc-NH2. This difference was reflected by the light irradiation experiments on the HL-60 cell line, in which aminoferrocene conjugated with the o-nitrobiphenyl cage and the MLS displayed the highest phototoxicity index (2.5 ± 0.4) of all the compounds tested. The iron release assays confirmed the rise in iron ion concentrations upon light irradiation of both caged aminoferrocene derivatives. Together with the absence of phototoxicity on the nonmalignant hTERT-immortalized retinal pigment epithelial (hTERT RPE-1) cell line, these results indicate catalytic generation of ROS as possible mode of action.
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Leonidova
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Anstaett
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.|Institute of Molecular Cancer Research, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pierroz
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mari
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Spingler
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D055668:Photochemical Processes; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
chemical_list: D005296:Ferrous Compounds