Salen−Manganese Complexes as Catalytic Scavengers of Hydrogen Peroxide and Cytoprotective Agents:  Structure−Activity Relationship Studies

Abstract

Synthetic catalytic scavengers of reactive oxygen species (ROS) may have broad clinical applicability. In previous papers, two salen-manganese complexes, EUK-8 and EUK-134, had superoxide dismutase (SOD) and catalase activities and prevented ROS-associated tissue injury. This study describes two series of salen-manganese complexes, comparing catalytic ROS scavenging properties and cytoprotective activities. The compounds vary widely in ability to scavenge hydrogen peroxide, with this activity most influenced by salen ring alkoxy substitution and aromatic bridge modifications. In contrast, all compounds show comparable SOD activities. The most active alkoxy-substituted catalase mimetics protected cultured cells from hydrogen peroxide, and a subset of these were also neuroprotective in a rodent stroke model. Thus, structural modification of the prototype EUK-8 yields compounds with enhanced catalase activity and, in turn, biological effectiveness. This supports the concept that salen-manganese complexes represent a class of SOD and, in particular, catalase mimetics potentially useful against ROS-associated diseases.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…In agreement with these calculations, Sharpe et al (284) considered Mn salens to be poor catalysts of H 2 O 2 breakdown (284). Although SOD-like activity is reportedly not dependent on the structure, the structure-activity relationship has been established for catalase-like activity (93,94). Alkoxy groups in position 3 (EUK-134, EUK-189) enhanced, whereas in position 5, decreased the catalase activity when compared with EUK-8 compound.…”

“…1). Although salen compounds have been of interest in catalysis since the beginning of the last century, the possible role of their Mn complexes in decreasing oxidative-stress injuries arose quite recently and parallels studies on another two groups of metal complexes, Mn cyclic polyamines and Mn porphyrins (40,93). EUK-8, the Mn salen (Mn(III) complex with prototypical N,N'-bis(salicylidene)ethylenediamine) (Fig.…”

Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses

“…Salen complexes are Schiff bases, usually prepared by the condensation of a salicylaldehyde with an amine. Based on the salen ring substitutes, EUKs are named from EUK-8 to EUK-189 and have different rates of SOD and catalase/peroxidase activities [76,77]. Treatment of RSVinfected airway epithelial cells with EUK-8, -134 and -189, which have SOD and catalase/peroxidase activity, results in significantly reduced ROS levels ( Figure 3A) and markers of oxidative cell damage ( Figure 3B).…”

The Supramolecular Attitude of Metal–Salophen and Metal–Salen Complexes

“…The N 2 O 2 coordination sphere reproduces the setting found for many metals in metalloproteins, since these ligands are structurally similar to porphyrins, but much easier to synthesize. Further, the possibility of incorporating two different benzylidene moieties and diamine backbones [3] provides access to a large variety of salen/salophen ligands that, after deprotonation of both phenolic oxygens, can form rather stable complexes with many transition and main group metals, with different oxidation states, coordination numbers and geometries that have shown interesting applications in many fields [4][5][6][7][8][9]. Recently also an extensive use of metal complexes with salen and salophen ligands has been reported in the design of new magnetic materials [10,11].…”