Superoxide dismutase mimic

The enzyme superoxide dismutase (SOD) occurs in three forms in mammalian systems (1) CuZnSOD (SOD1) found in the cytosol, (2) MnSOD (SOD2) found in mitochondria, and (3) CuZnSOD found in extracellular space (SOD3). Additionally, many bacterial SOD enzymes contain iron. SOD 1 has been discussed in detail 

Section 5.2.3 in Chapter 5. Superoxide dismutase enzymes catalyze dismutation of the superoxide anion radical (O2 ) according to the summary reactions in equation 7.1  

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210  

Many transition metal complexes have been considered as synzymes for superoxide anion dismutation and activity as SOD mimics. The stability and toxicity of any metal complex intended for pharmaceutical application is of paramount concern, and the complex must also be determined to be truly catalytic for superoxide ion dismutation. Because the catalytic activity of SOD1, for instance, is essentially diffusion-controlled with rates of 2 x 1 () M 1 s 1, fast analytic techniques must be used to directly measure the decay of superoxide anion in testing complexes as SOD mimics. One needs to distinguish between the uncatalyzed stoichiometric decay of the superoxide anion (second-order kinetic behavior) and true catalytic SOD dismutation (first-order behavior with [O ] [synzyme] and many turnovers of SOD mimic catalytic behavior). Indirect detection methods such as those in which a steady-state concentration of superoxide anion is generated from a xanthine/xanthine oxidase system will not measure catalytic synzyme behavior but instead will evaluate the potential SOD mimic as a stoichiometric superoxide scavenger. Two methodologies, stopped-flow kinetic analysis and pulse radiolysis, are fast methods that will measure SOD mimic catalytic behavior. These methods are briefly described in reference 11 and in Section 3.7.2 of Chapter 3. 

Mn(II) ions complexed by porphyrinato(2 ) ligands have shown catalytic superoxide anion dismutation. One SOD mimic, M40403, complexes Mn(II) via a macrocyclic ligand, 1,4,7,10,13-pentaazacyclopentadecane, containing added bis(cyclohexyl) and pyridyl functionalities. M40403 carries the systematic name [manganese(II) dichloro] 4R,9R, 14/s, 19/ )-3,10,13,20,26-pentaazatetracyclo[20.3. 1.0(4,9)0(14,19)]hexacosa-l(26),-22(23),24-triene ]. The molecule is shown in 

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Baudry, M., Etienne, S., Bruce, A., Palucki, M., Jacobsen, E. and Malfroy, B. (1993). Salen-manganese complexes are superoxide dismutase-mimics. Biochem. Biophys. Res. Commun. 192, 964-968. 

Beyer, W.F. and Fridovich, I. (1989). Characterization of a superoxide dismutase mimic prepared from desferrioxamine and MnOa. Arch. Biochem. Biophys. 271, 149-156. 

Weiss, R. Riley, D. Therapeutic Aspects of Manganese(II)-based Superoxide Dismutase Mimics In Uses of Inorganic Chemistry in Medicine, Farrell, N., Ed. The Royal Society of Chemistry Cambridge, 1999, pp 77-92. 

Several reports indicate the involvement of superoxide in the mediation of tolerance [67-69]. Based on these reports, a bifunctional superoxide dismutase-mimic NO donor was designed by Haj-Yehia s group [70]. The nitrate ester was incorporated into a nitroxide such as 3-hydroxymethyl-2,2,5,5-tetramethyl-l-pyrroHdinyloxy (HMP) by its conversion into 3-nitratomethyl-PROXYL (NMP) (Scheme 1.7). HMP is a stable, metal-independent, low-molecular weight SOD-mimic with excellent cell-permeability. So NMP is the first compound that can simultaneously generate NO and destroy superoxide. This may lead to novel nontolerance-inducing nitrovasodila-tors. 

Riley, D.P. Rational design of synthetic enzymes and their potential utility as human pharmaceuticals development of manganese(II)-based superoxide dismutase mimics. Adv. Supramol. Chem. 2000, 6, 217-244. 

Riley, D.P., Henke, S.L, Lennon, P.J., Aston, K. Computer-aided design (CAD) of synzymes use of molecular mechanics (MM) for the rational design of superoxide dismutase mimics. Inorg. Chem. 1999, 38(8), 1908-1917. 

Barik A, Mishra B, Shen L, Mohan H, Kadam RM, Dutta S, Zhang HY, Priyadarsini KI. 2005. Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its free radical reactions. Free Radio Biol Med 39 811-822. 

Ries, W.L., Key, L.L., and Rodriguiz, R.M. 1992. Nitroblue tetrazolium reduction and bone resorption by osteoclasts in vitro inhibited by a manganese-based superoxide dismutase mimic. J. Bone Miner. Res. 7, 931-938. 

Baudry M et al (1993) Salen-manganese complexes are superoxide dismutase-mimics. Biochem Biophys Res Com 192 964-968... 

Nagano T, Hirano T, Hirobe M. Superoxide dismutase mimics based on iron in vivo. J Biol Chem 1989 264 9243-9. 

Some metal- (especially copper) complexes catalyse the dismutation of superoxide at rates that compare favourably with catalysis by superoxide dismutase. One could therefore argue that the presence of such complexes in vivo might be beneficial. There are, however, additional considerations (1) such metal complexes may also reduce hydrogen peroxide, which could result in the formation of hydroxyl radicals, and (2) it is extremely likely that the metal will be displaced from its ligands (even when those ligands are present in excess), and becomes bound to a biomolecule, thereby becoming less active as a superoxide dismutase mimic. As an example, copper binds well to DNA and catalyses the formation of hydroxyl radicals in the presence of hydrogen peroxide and ascorbate [30],... 

Fig. 1. The effect of the low-molecular-weight superoxide dismutase mimic, CuDIPS, on human carcinoma (HeLa) cell growth. Monolayer cultures (0.5 x 10 6 cells/plate) were established by growth overnight in Eagles MEM medium supplemented with 10% calf serum. The medium was removed and replaced with fresh medium containing 0.1% ethanol or varying amounts of CuDIPS [copper II-(3,5-diisopropylsalicylate)2] in 0.1% ethanol. After 3 days the number of live cells per plate were assessed as described in ref. [44], The results are expressed as means of triplicate experiments s.d.

DEVELOPMENT OF MANGANESE(II)-BASED SUPEROXIDE DISMUTASE MIMICS... 

RATIONAL DESIGN OF SYNTHETIC ENZYMES AND THEIR POTENTIAL UTILITY AS HUMAN PHARMACEUTICALS DEVELOPMENT OF MANGANESEdD-BASED SUPEROXIDE DISMUTASE MIMICS Dennis P. Riley... 

Batinic-Haberle I, Liochev SI, Spasojevic I, Fridovich I. A potent superoxide dismutase mimic manganese beta-octabromo-meso-tetrakis-(V-methylpyridinium-4-yl) porphyrin. Arch Biochem Biophys 1997 343 225-233. 

Design of Manganese-based Superoxide Dismutase Mimics... 

Advantages of Superoxide Dismutase Mimics over Superoxide Dismutase Enzymes... 

REACTIVITY OF MANGANESE SUPEROXIDE DISMUTASE MIMICS TOWARD SUPEROXIDE AND NITRIC OXIDE SELECTIVITY VERSUS CROSS-REACTIVITY... 

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