Salen-Manganese Complexes Are Superoxide Dismutase-Mimics

doi:10.1006/bbrc.1993.1509

Biochemical and Biophysical Research Communications

Volume 192, Issue 2, 30 April 1993, Pages 964-968

https://doi.org/10.1006/bbrc.1993.1509 Get rights and content

Abstract

Complexes of manganese have previously been shown to exhibit SOD activity. In this study, we tested the ability of several (salen)-manganese complexes to scavenge O₂^.. Both neutral and cationic complexes were determined to be SOD-mimics. The activity of the complexes was not affected by the presence of bovine serum albumin in the assay. For most compounds, the activity was inhibited by the addition of EDTA. The stability and high catalytic activity of some of these molecules suggest that they might have potential use in a variety of conditions which involve overproduction of oxygen free radicals.

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Cited by (208)

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Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O _{2 -}.) into molecular oxygen (O ₂) and hydrogen peroxide (H ₂O ₂) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease (HD), Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.
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Much research has been done on traditional homogeneous metal catalysts and enzymatic catalysts, but recently a new class of hybrid catalysts called synthetic (artificial) metalloenzymes has been considered by researchers. Metalloenzymes as hybrid catalysts (host-guest systems) have been shown that combine the properties of a homogeneous and also enzymatic catalyst. The hybrid catalyst will have added value such as enantioselectivity or chemo-selectivity. This review focuses on Schiff base complexes that either act as homogeneous artificial enzymes or contribute to the structure of a host in the preparation of hybrid metalloenzymes. Because this approach can virtually be applied to any bio- or synthetic host or guest coordination complex, the details of hybrid catalysts seem important for advance in catalysis.
Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models
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Oxidative stress that results from an imbalance between the concentrations of reactive species (RS) and antioxidant defenses is associated with many pathologies. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase are among the key enzymes that maintain the low nanomolar physiological concentrations of superoxide and hydrogen peroxide. The increase in the levels of these species and their progeny could have deleterious effects. In this context, chemists have developed SOD and CAT mimics to supplement them when cells are overwhelmed with oxidative stress. However, the beneficial activity of such molecules in cells depends not only on their intrinsic catalytic activities but also on their stability in biological context, their cell penetration and their cellular localization. We have employed cellular assays to characterize several compounds that possess SOD and CAT activities and have been frequently used in cellular and animal models. We used cellular assays that address SOD and CAT activities of the compounds. Finally, we determined the effect of compounds on the suppression of the inflammation in HT29-MD2 cells challenged by lipopolysaccharide. When the assay requires penetration inside cells, the SOD mimics Mn(III) meso-tetrakis(N-(2′-n-butoxyethyl)pyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP⁵⁺) and Mn(II) dichloro[(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-eicosahydro-11,7-nitrilo-7Hdibenzo[b,h] [1,4, 7,10] tetraazacycloheptadecine-κN5,κN13,κN18,κN21,κN22] (Imisopasem manganese, M40403, CG4419) were found efficacious at 10 μM, while Mn(II) chloro N-(phenolato)-N,N′-bis[2-(N-methyl-imidazolyl)methyl]-ethane-1,2-diamine (Mn1) requires an incubation at 100 μM. This study thus demonstrates that MnTnBuOE-2-PyP⁵⁺, M40403 and Mn1 were efficacious in suppressing inflammatory response in HT29-MD2 cells and such action appears to be related to their ability to enter the cells and modulate reactive oxygen species (ROS) levels.
Synthesis, characterisation and cytotoxic activity evaluation of new metal-salen complexes based on the 1,2-bicyclo[2.2.2]octane bridge
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(R)-1,2-Diaminobicyclo[2.2.2]octane was used as a starting material for the preparation, in solution or in a ball mill, of a salen ligand. Five metal salen complexes were prepared in high yield and their cytotoxic activities were evaluated against the Human Colon cancer HCT116 cell lines. The original manganese salen complex displayed the highest activity with a potency 16 fold higher than that of cisplatin, demonstrating the benefit of the bridging backbone compared to other salen systems. An alternative preparation route for this complex by mechanochemistry was also performed.
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Citation Excerpt :
Manganese compounds can act as antioxidants against superoxides (O2–), which are produced as a part of normal metabolism in human body [2]. There are three major classes of manganese complexes with MnSOD-like (manganese superoxide dismutase) activity: manganese(III) porphyrin compounds, manganese(III) salens, and manganese(II) pentaazamacrocycles [3–11]. In particular, complex M40403 (Fig. 1) has been investigated in a significant number of preclinical studies on animals and human cells against oral mucositis, myocardial ischemia-reperfusion injury, inflammation, and cerebral ischemia reperfusion injury and considered as a leading clinical candidate against Parkinson disease [12–17].
Mixed-ligand manganese(II) complexes [Mn₃(bipy)₂L₄(OAc)₂] (1), [Mn₂(dmbipy)₂L₂(OAc)₂] (2) and [Mn(dmphen)₂L₂] (3), where L – 5-phenyltetrazolate anion, bipy – 2,2′-bipyridine, dmbipy – 2,2′-bi-4-picoline, dmphen – 4,7-dimethyl-1,10-phenanthroline, have been synthesized and characterized by elemental analysis, IR spectroscopy, cyclic voltammetry and powder X-ray diffraction. Single‐crystal X‐ray diffraction analysis was carried out to determine crystal structures of complexes. The UV-vis spectroscopy has been applied to show the stability of the compounds in solution. The effect of the compounds on viability of HepG2 and Hep-2 cell lines has been investigated. Complex [Mn(dmphen)₂L₂] was found to be the most cytotoxic with IC₅₀ values of 5.7 ± 0.6 µM (HepG2 cells) and 8.1 ± 1.2 µM (Hep-2 cells). The antimicrobial activity of complexes and ligands has been investigated against E. coli, S. aureus, P. italicum and C. steinii. All complexes have shown protistocidal activity against C. steinii. Complexes have been found to exhibit antioxidant activity measured spectrophotometrically using ABTS^•⁺ radical.
Salen‑manganese complexes for controlling ROS damage: Neuroprotective effects, antioxidant activity and kinetic studies
2020, Journal of Inorganic Biochemistry
Citation Excerpt :
In this context, efforts have been directed toward the search of antioxidant enzyme mimics [7–9]. This research determination has often focused on manganese complexes with Schiff bases as Mn ions do not induce Fenton chemistry [10–16]. It is well established that these complexes protect cells from oxidative damage in animal models and lead to benefits in AD and PD, stroke, motor neuron disease, multiple sclerosis, and excitotoxic neural injury [17–19].
A new manganese(III) complex [MnL¹(DCA)(H₂O)](H₂O)_, 1 [H₂L¹ is the chelating ligand N,N′-bis(2-hydroxy-3-methoxybenzylidene)-1,2-diaminopropane, and DCA is dicyanamide], has been prepared and characterized by different analytical and spectroscopic techniques. The tetragonally elongated octahedral geometry for the manganese coordination sphere was revealed by X-ray diffraction studies for 1. The antioxidant behavior of this complex and other manganese(III)-salen type complexes was tested through superoxide dismutase and catalase probes, and through the study of their neuroprotective effects in SH-SY5Y neuroblastoma cells. In this human neuronal model, these model complexes were found to improve cell survival in an oxidative stress model. During studies aimed to getting a better understanding of the kinetics of the processes involved in this antioxidant behavior, an important effect on the solvent in the kinetics of reaction of the complexes with H₂O₂ was revealed that suggests a change in the mechanism of reaction of the complexes. The kinetic data in methanol and buffered aqueous solutions correlate well with the results of the test of catalase activity, thus showing that the rate determining step in the catalytic cycle corresponds to the initial reaction of the complexes with H₂O₂.

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Regular ArticleSalen-Manganese Complexes Are Superoxide Dismutase-Mimics

Abstract

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Salen-Manganese Complexes Are Superoxide Dismutase-Mimics