Chimie médicale

Cellular Redox State Modifications Induced by Bioactive Fe(III)-Cyclophane Complexes Approaching to Selective Therapy Drug Design

Abstract

Alex J Salazar-Medina, Efrain Alday, Ana L Carreño, Javier Hernandez, Gustavo A González-Aguilar, Carlos Velázquez and Enrique F Velázquez-Contreras

Previously we reported the capacity of the bio-inspired Fe(III) complexes, Fe2PO and Fe2PC, to mimic the activity of superoxide dismutase and peroxidase enzymes, as well as their capacity to reduce the cytotoxicity generated by superoxide radicals in human peripheral blood mononuclear cells, under stress conditions. Based on those findings, we decided to evaluate the cytotoxicity, antioxidant and redox state modulation capacity of Fe2PO and Fe2PC complexes, pondering them as drug candidates against free radicals unbalance disorders. Fe2PO and Fe2PC deactivated the ABTS synthetic radical with an IC50 value of 38.4 ± 0.9 μM and 28.9 ± 0.2 μM, respectively, while against the DPPH radical, the IC50 value was over the higher concentration tested (>200 μM) for both complexes. As desirable for any drug candidate, none of the metallic complexes (at 25, 50 and 100 μM) induced cytotoxicity on M12.C3.F6 cells (a murine B-cell lymphoma model), but differences in the redox state modulation were observed on the basis of fluorescence detection of a 2′,7′-dichlorofluorescin probe by flow cytometry. Cells under normal conditions and preincubated with Fe2PO and Fe2PC complexes slightly augmented the reactive oxygen species concentration, meanwhile, cells under stress condition preincubated with H2O2 and metallic complexes, showed a higher augmentation in the reactive oxygen species concentration, in comparison to the controls. Finally, a cellular internalisation assay was performed, showing that Fe2PO and Fe2PC exert those effects from the outside of the cells. All these results suggest the ability of Fe2PO and Fe2PC complexes to selectively increase the reactive oxygen species concentration in cells with a free radical unbalance, without inducing mortality in cells under normal conditions.