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

Abstract

Previously we reported the capacity of the bio-inspired Fe(III) complexes, Fe 2 PO and Fe 2 PC, 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 Fe 2 PO and Fe 2 PC complexes, pondering them as drug candidates against free radicals unbalance disorders. Fe 2 PO and Fe 2 PC deactivated the ABTS synthetic radical with an IC 50 value of 38.4 ± 0.9 µM and 28.9 ± 0.2 µM, respectively, while against the DPPH radical, the IC 50 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 Fe 2 PO and Fe 2 PC complexes slightly augmented the reactive oxygen species concentration, meanwhile, cells under stress condition preincubated with H 2 O 2 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 Fe 2 PO and Fe 2 PC exert those effects from the outside of the cells. All these results suggest the ability of Fe 2 PO and Fe 2 PC complexes to selectively increase the reactive oxygen species concentration in cells with a free radical unbalance, without inducing mortality in cells under normal conditions.

Immune response of human cultured cells towards macrocyclic Fe2PO and Fe2PC bioactive cyclophane complexes

“…The harmlessness of Fe 2 PO and Fe 2 PC was been observed previously in human and murine systems (Salazar-Medina et al, 2013;Salazar-Medina et al, 2017) and the current work's findings improve our understanding of how cyclophane metal complexes can exert bioactive properties as antioxidants, without inducing cell mortality.…”

“…The Fe 2 PO and Fe 2 PC complexes have been widely studied as antioxidants against synthetic free radicals using in vitro systems, reducing oxidative stress in human peripheral blood mononuclear cells and in murine cell lines (Salazar-Medina et al, 2013, 2017. Also, their ability to mimic the activity of the enzymes superoxide dismutase and peroxidase has been demonstrated by in vitro assays.…”

Syntheses, Characterization, and Antioxidant Evaluation of Cu2+, Mn2+, and Fe3+ Complexes with a 14 Membered EDTA-Derived Macrocycle

“…High activities against ABTS were reported for macrocyclic binuclear metal complexes: IC 50 = 10 ± 0.6 µM and 18 ± 0.5 µM for Cu 2+ complexes Cu 2 PO and Cu 2 PC (Figure 5), respectively [6], and 38 ± 0.9 µM and 28 ± 0.2 µM for Fe 3+ complexes Fe 2 PO and Fe 2 PC (Figure 5) [15]. These complexes are inhibitors as powerful as ascorbic acid (IC 50 = 14.9 ± 0.5 µM), although the inhibitory capacities are moderate when compared with glutathione (<12.5 µM) and caffeic acid phenethyl ester (<12.5 µM).…”

Peer Review #1 of "Immune response of human cultured cells towards macrocyclic Fe2PO and Fe2PC bioactive cyclophane complexes (v0.1)"

“…However, a compound, natural or synthetic, could affect the gene expression of cells, often through immunologic pathways. We used human embryonic kidney (HEK) 293T cells exposed to the metal complexes Fe 2 -2,9,25,32-tetraoxo- 4 The Fe 2 PO and Fe 2 PC complexes have been widely studied as antioxidants against synthetic free radicals using in vitro systems, reducing oxidative stress in human peripheral blood mononuclear cells and in murine cell lines [3,5]. Also, their ability to mimic the activity of the enzymes superoxide dismutase and peroxidase has been demonstrated by in vitro assays.…”