Antioxidant capacity of binuclear Cu(II)‐cyclophanes, insights from two synthetic bioactive molecules

Abstract

The compounds 2,9,25,32-tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10,24,27,30,33-octaaza-17,40-dioxa[10.1.10.1]paracyclophane and 2,9,25,32-tetraoxo-4,7,27,30-tetrakis(carboxymethyl)-1,4,7,10,24,27,30,33-octaaza[10.1.10.1]paracyclophane binuclear copper complexes (Cu2PO and Cu2PC, respectively) were studied by determining their antioxidant capacity using the TROLOX equivalent antioxidant capacity (TEAC) assay, and their cytotoxicity on cultured cells, as well as the superoxide dismutase (SOD)-like activity. Cu2PO had an antioxidant capacity (0.1 g eq TROLOX mol−1) within the order of magnitude of ascorbic acid, and both, Cu2PO and Cu2PC were nontoxic to cultured peripheral mononuclear blood cells. The SOD-like activity was evaluated using the nitroblue tetrazolium assay, and both compounds presented an excellent activity: for Cu2PO, the IC50 was 52 nM and for Cu2PC an IC50 of 0.5 μM was obtained comparable to CuZn SOD IC50 17 nM (Fernandes et al., J Inorg Biochem 2007;101:849–858). These results suggest that synthetic binuclear macrocycles are good candidates to be used as synthetic bioactive molecules with applications in biomedicine.

Antioxidant Capacity of Two Novel Bioactive Fe(III)-Cyclophane Complexes

“…We previously evaluated the toxicity after 24 h culture of the Fe(III)-cyclophane complexes and the highest percentages of mortality for Fe 2 PO and Fe 2 PC was 0.9% and 0.5%, respectively. These results are similar to those previously reported by our group [ 5 ], where we found no toxic but a protective effect of the Cu 2 PO and Cu 2 PC in PBMCs by reducing mortality in 6% compared to control untreated cells. These results indicate that both cyclophane-Fe(III) complexes were not cytotoxic during the first 24 h of culture, even when high doses were used.…”

“…The Fe 2 PO had more antioxidant capacity (0.0690 g eq Trolox mol −1 ) than Fe 2 PC (0.0443 g eq Trolox mol −1 ), both within the range of the antioxidant capacity presented by ascorbic acid at the same molar concentration (0.0755 g eq Trolox mol −1 ) ( Figure 7 ). The behavior of the Fe(III) complexes was similar to the observed for the Cu(II) complexes reported by Sugich-Miranda and co-workers [ 5 ]. The difference between Fe 2 PO and Fe 2 PC antioxidant capacity could be due to differences in conformational flexibility of Fe 2 PC , resulting in a less favorable interaction with the ABTS •+ radicals in solution causing a lower antioxidant capacity.…”

“…The first line of defense against ROS in cellular systems is superoxide dismutase (SOD), that catalyzes the conversion of O 2 •− to H 2 O 2 and O 2 [ 4 ]. Some macrocyclic complexes have been proposed as SOD mimetics, mainly because of their high thermal stability and flexible ligand arrangement that allows redox processes based on their metal centers [ 5 ]. The action of SOD produces H 2 O 2 by the O 2 •− dismutation, a much less reactive molecule compared to O 2 •− , but still toxic to the cell.…”

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

“…Given the structural resemblance of the synthesised Fe(III) and Cu(II) binuclear macrocycle complexes to the active site of some metalloenzymes, we demonstrated the ability of these complexes to act as mimickers of SOD and PO enzymes [7,8]. In addition, these Fe(III) and Cu(II) complexes provided protection to human peripheral blood mononuclear cells (PBMC) under stress conditions by acting as superoxide scavengers [7,8].…”

“…A series of metallic complexes of Fe(III) and Cu(II) [7,8], based on cyclophane macrocycles as scaffolds [9], has been previously synthesised and reported by our research group. Given the structural resemblance of the synthesised Fe(III) and Cu(II) binuclear macrocycle complexes to the active site of some metalloenzymes, we demonstrated the ability of these complexes to act as mimickers of SOD and PO enzymes [7,8].…”