Salen- Manganese Complexes: Combined Superoxide Dismutase/Catalase Mimics with Broad Pharmacological Efficacy

Abstract

Publisher Summary Molecular oxygen, although essential for aerobic metabolism, can be converted to potentially deleterious substances, including superoxide ion, hydrogen peroxide, and hydroxyl radical, known collectively as reactive oxygen species (ROS). Increased ROS formation under pathological conditions is believed to cause cellular damage through chemical interactions with proteins, lipids, and DNA. Some degree of tissue protection is provided by endogenous ROS scavengers such as superoxide dismutases (SOD) and catalase, which catalytically destroy superoxide ion and hydrogen peroxide, respectively. Also, molecules synthesized endogenously or acquired through diet, such as ascorbate (vitamin C), α-tocopherol (vitamin E), and glutathione, have antioxidant properties. Salen-manganese complexes, the focus of this chapter and porphyrin-manganese complexes have been reported to have SOD activity. Synthetic salen-manganese has catalase activity as well. Salen-manganese complexes have characteristics that might facilitate their potential usefulness as therapeutic agents. First, as low molecular weight, synthetic molecules rather than proteinaceous antioxidant enzymes they have the potential advantages that relate to cost-effectiveness and pharmaceutical formulation and delivery. Second, they act catalytically, presumably enhancing their efficiency over noncatalytic low-molecular-weight ROS scavengers. Third, their ability to destroy both superoxide anion and hydrogen peroxide should enhance their protective potential in various disease states involving the production of multiple ROS species. In this chapter are described the catalytic properties of EUK-8, a prototype salen-manganese complex, the efficacy of EUK-8 in experimental models for disease and the future directions in the development of salen–manganese complexes as novel, broadly applicable potential therapeutic agents. The chapter discusses how EUK-8 and other salen–manganese complexes exhibit superoxide scavenging activity, the catalase activity of EUK-8: catalatic and peroxidatic reaction pathways, how salen–manganese complexes have advantages over other antioxidants, and how EUK-8 is protective in a model for adult respiratory distress syndrome and neurological disorders. Salen–manganese complexes have a novel mode of action and an extremely broad potential clinical utility.