Superoxide dismutase (SOD) mimetics are synthetic compounds that mimic the native superoxide dismutase enzyme.[1] SOD mimetics effectively convert the superoxide anion (O−
2), a reactive oxygen species, into hydrogen peroxide, which is further converted into water by catalase.[2] Reactive oxygen species are natural byproducts of cellular respiration and cause oxidative stress and cell damage, which has been linked to causing cancers, neurodegeneration, age-related declines in health, and inflammatory diseases.[3][4] SOD mimetics are a prime interest in therapeutic treatment of oxidative stress because of their smaller size, longer half-life, and similarity in function to the native enzyme.[3][5][6]
The chemical structure of SOD mimetics generally consists of manganese, iron, or copper (and zinc) coordination complexes.[1][3][7] Salen-manganese(III) complexes contain aromatic ring structures that increase the lipid solubility and cell permeability of the entire complex.[2] Manganese (II) and iron (III) complexes are commonly used due to their high kinetic and thermodynamic stability, increasing the half-life of the mimetic.[1] However, manganese-based SOD mimetics are found to be more therapeutically effective than their counterparts due to their low toxicity, higher catalytic activity, and increased stability in vivo.[1][3][7]
Similar to the native enzyme’s mechanism,[8] the manganese complexes undergo a reversible oxidation/reduction cycle.[2] In the first half reaction manganese covalently coordinates to the superoxide anion on its oxygen binding site,[2] through inner-sphere electron transfer.[3] (Mn) is reduced by superoxide, yielding molecular oxygen and a reduced form of manganese (Mn-1). The metal (Mn-1) is then regenerated to its former oxidation state (Mn) by reducing a second superoxide molecule to hydrogen peroxide.[9]
The metal complex must be electron deficient in nature, allowing it to accept electrons from the superoxide.[10] This is accomplished by coordinating electron-withdrawing ligands around the metal center.[10] Since the mechanism of SOD mimetics involves a redox cycle, the catalytic activity of the SOD mimetic is partially dependent on the reduction potential of the metal center.[9] Coordinated ligands of SOD mimetics fine-tune the chemical properties of the complex[3] and are designed to match the 300mV reduction potential of the native enzyme.[11]
The most prominent SOD mimetics are: manganese porphyrin complexes, manganese (II) penta-azamacrocyclic complexes, and manganese (III) salen complexes.[4]
Porphyrin SOD mimetics consist of manganese (III) centers coordinated by a single porphyrin ring.[10] Although both complexes are effective porphyrin-based superoxide dismutases, MnTBAP [Mn(III)tetrakis (4-benzoic acid) porphyrin] was shown to better protect the cells from oxidative damages compared to ZnTBAP ((Zinc (III) tetrakis (4-benzoic acid)porphyrin chloride)) in vivo.[7] Researchers found MnTBAP reversed obesity[12] and induced faster wound healing in diabetic mice.[13] MnTBAP has the ability to prevent formation of cytotoxic peroxynitrite,[14] a hazardous byproduct of superoxide reacting with nitric oxide, and induces healing process of wounds.[13] MnTMPyP [manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin], another porphyrin molecule, was also found effective in relieving oxidative stress caused by peroxynitrite in intracellular and extracellular conditions.[15] Manganese-porphyrin complexes reduced the damaging effects of radiation treatment in mice.[4]
M40403 and M40401 are Manganese (II) Penta-Azamacrocyclic complexes with SOD mimetic properties.[16] Mn (II) complexes are found to be more stable in vivo and have high specificity for the superoxide anion, preventing unwanted interactions with biologically important molecules.[1] They are characterized as having a small size, high stability, and higher catalytic efficiency than superoxide dismutase, especially in more acidic environments.[1][16] M40403 was found effective in reducing oxidative tissue damage induced by total body irradiation.[16] M40401 is similar in structure to M40403, but it has two additional methyl groups, causing a one hundredfold increase in catalytic activity in treatment of ischemia-reperfusion injuries.[17] M40401 was also found to protect against hypoxic-ischemic brain injury.[6]
Mn (III) Salen complexes are found to be more stable than other iron or manganese mimics of superoxide dismutase.[2] In certain synthesized forms, aromatic rings are coordinated with the manganese center, increasing the lipid solubility of the entire complex, allowing it to pass the cellular membrane.[2]
Treatment of the nematode Caenorhabditis elegans with superoxide dismutase/catalase (SOD/catalase) mimetics has been reported to extend life-span.[18][19] Mice with deficient SOD2 die prematurely, exhibiting severe metabolic and mitochondrial defects. Treatment of such mice with SOD/catalase mimetics extended their life-span by as much as three-fold.[20] Treatment of wild-type mice with a carboxyfullerene SOD mimetic not only reduced age-associated oxidative stress and mitochondrial radical production, but significantly extended life-span.[5] This treatment also rescued age-related cognitive impairment. These findings suggest that oxidative stress is an important determinant of life-span.