ANTI-OXIDATIVE AND ANTI-INFLAMMATORY METAL:PEPTIDE COMPLEXES AND USES THEREOF

Abstract: Metal:peptide complexes possessing anti-oxidative and anti-inflammatory activity are disclosed. The complexes can be used as active therapeutic substances, in pharmaceutical preparations to inhibit oxidative and inflammatory processes which can lead to tissue damage, and in the manufacture of medicaments for enhancing or restoring the resistance of warm-blooded animals to oxidative or inflammatory damage caused by release of reactive oxygen species by certain immune cells or other physiological processes. Metal:peptide:chelating agent complexes are also disclosed.

Description: Description ANTI-OXIDATIVE AND ANTI-INFLAMMATORY METALrPEPTIDE COMPLEXES AND USES THEREOF Technical Field The present invention relates generally to metalrpeptide complexes and uses thereof, and more particularly, to metalipeptide complexes which possess anti-oxidative and anti-inflammatory activity. Background of the Invention Highly reactive oxygen species such as superoxide anion (O2 " ), hydrogen peroxide (H2O2), hydroxyl radical ("OH), and lipid peroxides (LOOH) are involved in a number of human diseases. For example, oxygen radicals have been implicated in autoimmune diseases, arthritis, tissue damage caused by environmental pollutants, cigarette smoke and drugs, tissue injury during surgery and transplantation, as well as a variety of other conditions (Halliwell, B., Fed. Amer. Soc. Exp. Biol. 1:358-364, 1987). Reactive oxygen species are also generated during the response to injury by phagocytic cells. One of the early events in the wound healing response is the cleansing and sterilization of the wound by neutrophils and macrophages. A mechanism for this sterilization is the generation of the highly reactive superoxide anion and hydrogen peroxide. Superoxide anion and hydrogen peroxide will, in the presence of iron or other redox active transition metal complexes, generate hydroxyl radical. The hydroxyl radical is a potent oxidant which will initiate the free radical oxidation of fatty acids and the oxidative degradation of other biomolecules. One of the most vital areas in which reactive oxygen species cause tissue damage is in post-injury damage to the brain and spinal chord, and in reperfusion injury to ischemic tissue following surgery and transplantation (e.g., the heart). A sudden inrush of oxygenated blood and activated phagocytic cells leads to superoxide anion and hydrogen peroxide formation. These species do direct damage to the tissue and also react with iron, as discussed above, to generate the very reactive hydroxyl radical. Iron has also been shown to have a direct role in the initiation of lipid peroxidation. An Fe(II)/Fe(III) complex can serve as an initiator of lipid oxidation. In addition, many iron complexes can catalyze the decomposition of lipid hydroperoxides to the corresponding lipid alkoxy radicals, which will 5 continue the peroxidation cascade. The major storage site for iron in serum and tissue is ferritin. This ubiquitous storage protein (M.W. ~ 450,000) can store up to 4500 atoms of iron per protein molecule. It has been shown that superoxide anion can promote the mobilization of iron from ferritin. This free iron may then catalyze lipid peroxidation and the conversion of superoxide anion to the more l o damaging hydroxyl radical. A mechanism for the generation of the hydroxyl radical is illustrated below: 15 Neutrophils, Reperfusion Injury 20 Superoxide Anion > Ferritin (Fe(ϋl) bound) (+) Fe(II) « Fe(II) free 25 Hydroxyl Radical lipid Peroxidation and Tissue Damage A number of therapeutic agents have been utilized to prevent or 35 hmit oxidative damage. For example, agents such as superoxide dismutase (a 32,000 Dalton molecular weight enzyme), anti-oxidants (such as Vitamin E and C), and transition metal chelators have been shown to eliminate these ions and prevent them from participating in free radical reactions. Additional compounds which possess anti-oxidative properties include glycyl-I.-histidyl-L- 0 lysine:copper(II) and certain derivatives thereof, U.S. Patent Nos. 4,760,051, 4,665,054 and 4,877,770, each of which are incorporated herein by reference. As mentioned above, due to the severity and incidence of disease states in which reactive oxygen species play a role, there is a need in the art for effective anti-oxidant agents. Desirably, such agents should eliminate reactive oxygen species, inhibit the mobilization of metal ions such as iron which may participate in the generation of such species, and be available at the site of injury or reactive species generation. Summary of the Invention Briefly stated, the present invention discloses metakpeptide complexes which possess anti-oxidative and anti-inflammatory activity. These complexes can be used as active therapeutic substances, in pharmaceutical preparations to inhibit oxidative and inflammatory processes which can lead to tissue damage, and in the manufacture of medicaments for enhancing or restoring the resistance of warm-blooded animals to oxidative or inflammatory damage caused by release of reactive oxygen species. The metakpeptide complexes of the present invention include compounds of the following general formulas designated A through I: A: [glycyl- histidyl-L-lysine-R]:metal wherein R is an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, L-prolyl-Xj-L- phenylalanyl-X2 or Xι-L-phenylalanyl-X2, where Xj and X2 are selected from the group consisting of L-valine, L-alanine and glycine, and where Xi and X2 are not both L-valine, (X3) n -]__-tιyptophaι_, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); B: [glycyl-Rι-R2-R3]:metal wherein Rl is selected from the , group consisting of L-histidyl, L-(3-W> histidyl and L-(5-W)-histidyl, where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R 2 is -NHCH((CI . ) n NH 3 + )CO- where n = 5-10; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-ttyptophan, where y = 1-4, L-prolyl-Xi-L- phenylalanyl-X2 or Xι-L-phenylalanyl-f 2- where Xi and X2 are selected from the group consisting of L-valine, L-alanin and glycine, and where Xi and X2 are not both L-valine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X- n, where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n * = 1-5; and metal is copper(ϋ) or manganese(II); C: [glycyl-Rι-R2-R3]:metal wherein Rl is selected from the group consisting of I_-(3-W)-histidyl and L- (5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is L-lysyl; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, L-prolyl-Xi-L- phenylalanyl-X2 or Xχ-L-phenylalanyl-X2, where Xj and X2 are selected from the group consisting of L-valine, L-alanine and glycine, and where X and X2 are not both L-valine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); D: [glycyl-Rι-R2-R3]:metal wherein Rl is selected from the group consisting of L-histidyl, L-(3-W)- histidyl and L-(5-W)-histidyl where W is an alkyl moiety contaimng from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is a basic amino acid such as arginine, a basic amino moiety such as cadaverine, spermine or spermidine, or a modified basic amino acid such as caprolactone; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6- 12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, L-prolyl-Xi-L- phenylalanyl-X2 or X-[-L-phenylalanyl-X2. where Xj and X2 are selected from the group consisting of L-valine, 1,-alanine and glycine, (X3) n -I_-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); E: [R-[-R2-glycine-R3J:metal wherein Ri is IΛysyl or -NHCH((CH 2 ) n NH3 + )CO- where n = 5-10; R2 is selected from the group consisting of L-histidyl, L-(3-W)- histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6- 12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tιyptophan, where y = 1-4, L-prolyl-Xj-L- phenylalanyl-X2 or Xι-L-phenylalanyl-X2- where Xi and X2 are selected from the group consisting of L-valine, L-alanine and glycine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n _= 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); F: [Rι-R2-R3-R4]:metal wherein Rl is I ysyl or -NHCH((CH 2 ) n NH3 + )CO- where n = 5-10; R2 is selected from the group consisting of L-histidyl, L-(3-W)- histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is a basic amino acid such as arginine, an amino moiety such as cadaverine, spermine or spermidine, or a modified basic amino acid such as caprolactone; R4 is hydrogen, -NH2- an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6- 12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, L-prolyl-Xi-L- phenylalanyl-X2 or Xl-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, L-alanine and glycine, (X3) n -L-tτyptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); G: [Rι-glycyl-R2-R3]:metal wherein Rl is selected from the group consisting of L-histidyl, L-(3-W)- histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is L-lysyl, -NHCH((CH2) n NH3 + )CO-, where n = 5-10, or a basic amino acid such as arginine, an amino moiety such as cadaverine, spermine or spermidine, or a modified basic amino acid such as caprolactone; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6- 12 carbon atoms, an aminoalkyl moiety contaimng from 1 to 18 carbon atoms, or is l-tryptophan, L-phenylalanine, L-leucine, L-isoleucine, (glycyl)y-I_-tryptophan, where y = 1-4, L-prolyl-X -L-phenylalanyl-X2 or Xι-L-phenylalanyl-X2, where Xl and X2 are selected from the group consisting of L-valine, I_-alanine and glycine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4- 20, or -(X4)n » where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); H: [L-aIanyl-Rι-R2-R3]:metal wherein R is selected from the group consisting of L-histidyl, l * -(3- )- histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R 2 is L-lysyl or -NHCH((CH2) n NH3 + )CO- where n = 5-10; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, L-prolyl-X -L- phenylalanyl-X2 or Xι-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, L-alanine and glycine, and where Xi and X2 are not both L-valine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n = 1-5; and metal is copper(II) or manganese(II); I: [glycyl-Rι-R2-R3]:metal wherein R is L-lysyl or -NHCH((CH2) n NH3 + )CO- where n = 5-10 R2 is selected from the group consisting of histidyl, L-(3-W)- histidyl and I_-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is hydrogen, -NH2 . an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbofF atoms, an aryloxy moiety containing from 6- 12 carbon atoms, an aminoallcyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tτyptophan, where y = 1-4, L-prolyl-X -L- phenylalanyl-X2 or Xχ-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, L-alanine and glycine, (X3) π -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and ft = 4-20, or -(X4) n - where X4 is a naturally occurring carbohydrate such as glucose, mannose, galactose, glucosamine or galactosamine and n * = 1-5; and metal is copper(II) or manganese(II); and J: [Rι-R2-R3_:metal wherein Rl is selected from the group consisting of l-histidyl, L(3-W)- histidyl and L-(5-W)-histidyl, where W is an alkyl moiety containing from 1 to 12 carbons atoms or an aryl moiety contaimng from 6-12 carbon atoms; R2 is L-lysyl, -NHCH((CH2) n NH3 + )CO- where n = 5-10, a basic amino acid such as L-arginine, or a hydrophobic amino acid such as L- phenylalanine, L-leucine, or isoleucine; and R3 is L-lysyl, -NHCH((CH 2 ) n NH3 + )CO- where n = 5-10, a basic amino acid such as L-arginine, an amino moiety such as cadaverine, speπnine or spermidine, a modified amino acid such as caprolactone, or a hydrophobic amino acid such as L-phenylalanine, L-leucine, L-isoleucine, or L-tryptophan; and metal is copperQI) or xaanganese(II). In another embodiment of the present invention, a chelating agent may be added to the metakpeptide complex to form a ternary metal:peptide:chelating agent complex. Suitable chelating agents include imidazole and imidazole containing compounds, such as histidine, and sulfur- containing amino acids, such as cysteine and methionine. The present invention also discloses methods for enhancing or restoring the resistance of a warm blooded animal to oxidative or inflammatory 5 damage caused by release of reactive oxygen species by certain immune cells and other physiological processes. The methods comprise administering to the animal a therapeutically effective amount of a metakpeptide complex of the present invention. In addition to the methods disclosed above, the complexes of the present invention may also be used for enhancing the wound healing process in 0 animals. Other aspects of the present invention will become evident upon reference to the following detailed description. Best Mode for Carrying out the Invention 5 The present invention discloses metakpeptide complexes which possess anti-oxidative and anti-inflammatory activity. These complexes find use in the enhancement and/or restoration of the defense of warm-blooded animals to oxidative and inflammatory damage caused by highly reactive oxygen species, and may be used in pharmaceutical preparations to inhibit oxidative and inflammatory o processes which can lead to tissue damage. The metakpeptide complexes of the present invention possess one or more of the following features for preventing oxidative damage to tissue, including: 5 1) Superoxide dismutase mimetic activity to remove reactive superoxide anion; 2) Inhibition of iron release from tissue storage sites to prevent formation of reactive hydroxyl radical; 0 3) Structural moieties to enhance lipid solubility of the compounds to increase availability at the site of lipid peroxidation reactions; and 5 4) Structural moieties to enhance binding to serum proteins and increase residence time of the compound at the site of injury. The metakpeptide complexes of the present invention include compounds of the general formulas designated A through I above. For example, 0 in Formula F if Ri is L-lysyl, R2 is L-histidyl, R3 is arginine, R4 is an n-octyl alkoxy moiety, and the metal is copper(II), the structure of the metakpeptide complex would be as follows: O(CH 2 ) 7 CH 3 :copper(ll) Similarly, if R4 were an aminoalkyl moiety containing three carbon atoms of the formula -NH(CH2)2CH3, the metakpeptide complex would have the following structure: NH(CH 2 ) 2 CH 3 :copper(ll) The chiral amino acids of the present invention have all been designated as the L form. However, one skilled in the art would readily appreciate that the D forms of the amino acids may be utilized as a substitute for the L forms. The peptides of the present invention may be synthesized either by solution chemical techniques or by solid phase techniques. The general procedure involves the stepwise addition of protected amino acids to build up the desired peptide sequence. Such methodology is well known to those skilled in the art. Illustrative syntheses of complexes of the present invention are presented in the examples hereinbelow. Within the present invention, one may utilize a molar ratio of peptide to metal of, for example, 1:1, 2:1 or greater (e.g., 3:1). Preferably, the peptide to metal molar ratio is 2:1. A significant molar excess of peptide to metal results in unbound (i.e., non-chelated) peptide. Such unbound peptide does not serve to restore or enhance the anti-oxidative or anti-inflammatory process. Moreover, metal in molar excess of the peptide is loosely bound and may inhibit rather than enhance or restore the anti-oxidative or anti-inflammatory process. In another embodiment of the present invention, a chelating agent may be added to the metakpeptide complex to form a ternary metakpeptidexhelating agent complex. Suitable chelating agents include imidazole or imidazole-containing compounds, such as histidine, and sulfur containing amino acids, such as cysteine or methionine. Thus, if the metakpeptide complex is glycyl- histidyl- lysine:copper(II), histidine may be added to yield the ternary complex glycyl- tøstidyl- lysine:copper(II):histidine. However, to form such a ternary complex, the molar ratio of metal to peptide to chelating agent must be considered. For example, if the ratio of peptide to metal is 2:1, the addition of a chelating agent to the metakpeptide complex, although possible, is difficult due to site occupancy by the peptide. However, by maintaining the ratio of peptide to metal near 1:1, a chelating group may readily be added to form the ternary complex. Preferably, the peptide to metal to chelating agent ratio is 1:1:1. Pharmaceutical preparations of the present invention may contain the metakpeptide complex in combination with inert ingredients for topical application (i.e., pharmaceutical acceptable diluents), or contain suitable inert ingredients for either oral or parenteral applications (i.e., pharmaceutically acceptable carriers). The diluent or carrier should not interact with the metakpeptide complex in a manner which significantly reduces the effectiveness thereof. An effective dosage of the pharmaceutical preparations of the present invention delivers approximately 0.01 to 10 mg of metakpeptide complex per kg body weight. Methods for encapsulating compositions (such as in a coating of hard gelatin) for oral administration are well known in the art (Baker, Richard, Controlled Release of Biological Active Agents. John Wiley and Sons, 1986, incorporated herein by reference). Suitable pharmaceutically acceptable carriers for parenteral application, such as intravenous, subcutaneous or intramuscular injection, include sterile water, physiological saline, bacteriostatic saline (saline containing 0.9 mg/ml benzyl alcohol) and phosphate-buffered saline. Pharmaceutical preparations of the present invention may also be topically applied in the form of liquids, containing pharmaceutically acceptable diluents such as saline and sterile water, or be applied as lotions, creams or gels, containing additional ingredients to impart the desired texture, consistency, viscosity and appearance. Such additional ingredients are familiar to those skilled in the art and include emulsifying agents such as non-ionic ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, organic or inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives, hydrophilic beeswax derivatives, hydrocarbon oils such as palm oil, coconut oil, mineral oil, cocoa butter waxes, silicon oils, pH balancers and cellulose derivatives. Topical administration of the pharmaceutical preparation may by accomplished by applying an amount of the preparation directly to the desired area, such as a wound or an inflamed area. The required dosage will vary according to the particular condition to be treated, the severity of the condition, and the duration of the treatment. When the pharmaceutical preparation is topically applied in the form of a lotion, cream or gel, the preparation may contain about 1% to about 20% of a penetration enhancing agent. Examples of penetration enhancing agents include dimethylsulfoxide (DMSO), urea and eucalyptol. In the case of a liquid pharmaceutical preparation to be applied topically, the concentration of penetration enhancing agent such as DMSO may comprise about 30% to about 80% of the pharmaceutical preparation. EXAMPLES To summarize the examples that follow, Examples 1-16 illustrate the synthesis of representative metakpeptide complexes of the present invention, Examples 17-21 illustrate the anti-oxidative activity of representative metakpeptide complexes of the present invention, and Examples 22-23 illustrate the inhibition of iron release from ferritin and the inhibition of lipid peroxidation by representative metalrpeptide complexes of the present invention. Specifically, Example 1 illustrates the preparation of metakpeptide complexes of the present invention by the addition of a metal chloride to the peptide. Example 2 illustrates the synthesis of glycyl-L-histidyl- lysine n-octyl ester. Example 3 illustrates (a) the synthesis of glycyl-L-histidyl-L-lysine n-steaiyl ester, and (b) the synthesis of glycyl-L-histidyl- lysine n-palmityl ester. Example 4 illustrates the synthesis of glycyl-Lhistidyl-L-lysine n-octyl amide. Example 5 illustrates the synthesis of glycyl-Lhistidyl-Llysyl-L-valyl- phenylalanyl-Lvaline. Example 6 illustrates the synthesis of Lalanyl-L-histidyl-L- lysine. Example 7 illustrates the synthesis of Llysyl-L-histidyl-glycine. Example 8 illustrates the synthesis of lysyl-Lhistidyl-glycine amide. Example 9 illustrates the synthesis of Llysyl-Lhistidyl-glycine n-octyl ester. Example 10 illustrates the synthesis of Llysyl-Lhistidyl-glycyl-Lvalyl-Lphenylalanyl-Lvaline. Example 11 illustrates the synthesis of glycyl-Lhistidyl-caprolactam. Example 12 illustrates the synthesis of Lhistidyl-glycyl-L-lysine. Example 13 illustrates the synthesis of L-histidyl-glycyl-Llysyl-Lphenylalanine. Example 14 illustrates the synthesis of L-histidyl-glycyl-L-lysyl-L-tryptophan. Example 15 illustrates the synthesis of L- histidyl-Llysyl-L-phenylalanine. Example 16 illustrates the synthesis of Lhistidyl- L-phenylalanyl-Llysine. Example 17 demonstrates the superoxide dismutase mimetic activity of representative metakpeptide complexes of the present invention containing peptides of a hydrophobic nature. Example 18 demonstrates the superoxide dismutase mimetic activity of representative metakpeptide complexes of the present invention in relation to modifications of the amino acid sequence. Example 19 demonstrates the superoxide dismutase mimetic activity of representative metakpeptide complexes of the present invention wherein the metal is copper(II) and manganese(II). Example 20 demonstrates the superoxide dismutase mimetic activity of representative metakpeptide complexes of the present invention containing additional chelating groups. Example 21 demonstrates the superoxide dismutase mimetic activity of representative metakpeptide complexes of the present invention containing albumin binding moieties. Example 22 demonstrates the inhibition of iron release by ferritin utilizing representative metakpeptide complexes of the present invention. Example 23 demonstrates the inhibition of lipid peroxidation utilizing representative metakpeptide complexes of the present invention. Although lysine is designated by the single letter "L" herein, for puposes of clarity, those skilled in the art will recognize that the single letter amino acid abbreviation for lysine is "K." Therefore, K may be substituted for L in the examples that follow. Source of Chemicals Chemicals and peptide intermediates utilized in the following examples may be purchased from a number of suppliers, for example: Sigma Chemical So., St. Louis, Missouri; Peninsula Laboratories, San Carlos, California; Aldrich Chemical Company, Milwaukee, Wisconsin; Vega Biochemicals, Tucson, Arizona; Pierce Chemical Co., Rockford, Illinois; Research Biochemicals, Cleveland, Ohio; Van Waters and Rogers, South San Francisco, California; and Bachem, Inc., Torrance, California. EXAMPLE 1 PREPARATION OF METALPEPTIDE COMPLEXES The metalφeptide complexes of the present invention may be synthesized by dissolving the peptide in distilled water, followed by the addition of purified metal chloride and a then adjusting the pH of the solution. For example, copper(II) complexes of glycyl-Lhistidyl-Llysine ("GHL") with a molar ratio of peptide to metal of 1:1, 2:1, or greater (e.g., 3:1), may be prepared by dissolving a given weight of GHL in distilled water (e.g., 50 mg/ml), and adding the desired molar amount of purified copper(II) chloride. The pH of the resulting peptide solution is then adjusted to about 7.0 by the addition of a sodium hydroxide solution. Similar metakpeptide complexes may be prepared with manganese(II) by substituting manganese(II) chloride for the copper(ϋ) chloride in the procedure described above. Alternatively, metal salts other than the metal chloride may be utilized, such as copper(II) acetate or copper(II) sulfate. EXAMPLE 2 SYNTHESIS OF GLYCYL-LHISTIDYL-LLYSINE OCTYL ESTER:COPPER (TO A mixture of N e -benzyloxycarbonyl-LLysine, n-octanol, benzene, and p-toluenesulfonic acid monohydrate was refluxed overnight using a Dean- Stark trap to remove water. After cooling, dry ethyl ether was added. The solution was then allowed to precipitate at 0°C overnight. A portion of the precipitate solid was added to 50 ml of potassium carbonate solution and 50 ml of dichloromethane. After extraction, the layers were separated and the organic phase was washed with water and bribe, then dried with anhydrous magnesium sulfate. Filtration, evaporation and purification by flash column chromatography gave n-octyl N e -benzyloxycarbonyl-Llysinate. The product was dissolved in tetrahydrofuran and mixed with N a -t- butyloxycarbonyl-N im -benzyloxycarbonyl-L-histidine, isobutyl chloroformate and N-methylmo holine. After evaporation, water and ethyl acetate were added. The product was extracted into the organic phase, which was dried with anhydrous magnesium sulfate. Filtration, evaporation, and purification by flash column chromatography gave n-octyl N a -t-butyloxycarbonyl-N ιm -benzylo_q * carbonyl-L- histidyl-N e -benzyloj_ycarbonyl-Llysinate. The product was dissolved in 50% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporated, forming n-octyl N 1111 - benzyloxycarbonyl-Lhistidyl-N e -benzyloxycarbonyl-Llysinate. This was dissolved in tetrahydrofuran, and isobutyl chloroformates, N-methylmorpholine and benzyloxycarbonylglycine were added to form n-octyl benzyloxycarbonylglycyl- N-* m -benzyloxycarbonyl-Lhistidyl-N e -benzyloxycarbonyl-Llysinate. This was dissolved in glacial acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant n-octyl ester of glycyl-L-histidyl-L-lysine was converted to the copper(II) complex by dissolving water and mixing with equimolar copper(II) acetate. The pH was raised to neutrality with sodium hydroxide. The solution was centrifuged at 20,000 C g for 1 hour at 3°C to remove poorly soluble material. The supernatant solution was lyophilized to obtain glycyl- Lhistidyl-Llysine n-octyl estencopper(II). EXAMPLE 3 SYNTHESIS OF GLYCYL-LHISTIDYL-L-LYSINE N-STEARYL ESTER:COPPERfm A mixture of N e -benzyloxycarbonyl-Llysine, n-stearyl alcohol, benzene, and p-toluenesulfonic acid monohydrate was refluxed overnight using a Dean-Stark trap to remove water. After cooling, dry propyl ether was added to increase the total volume sixfold. The product was allowed to precipitate at 0°C overnight and filtered. A portion of the precipitate solid was added to 50 ml of potassium carbonate solution and 50 ml of dichloromethane. After extraction, the layers were separated and the organic phase was washed with water and brine, then dried with anhydrous magnesium sulfate. Filtration, evaporation and purification by flash column chromatography gave n-stearyl N e - benzyloxycarbonly-Llysinate. The product was dissolved in tetrahydrofuran and mixed with N a -t- butyloxycarbonyl-N-^-benzyloxycarbonyl-Lhistidine, isobutyl chloroformate and N-methylmorpholine. After evaporation, water and propyl acetate were added. The product was extracted into the organic phase, which was dried with anhydrous magnesium sulfate. Filtration, evaporation, and purification by flash column chromatography gave n-stearyl N^t-butylojycarbonyl-N-^-benzyloxycarbonyl-L- histidyl-N e -benzyloxycarbonyl-Llysinate. This was dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methylmorpholine and benzyloxycarbonylglycine were added to form n-stearyl benzyloxycarbonylglycyl-N ιm -benzyloxycarbonyl-L- histidyl-N e -benzyloxycarbonyl-Llysinate. The product was dissolved in glacial acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant n-stearyl ester of glycyl-Lhistidyl-Llysine was converted to the copper(II) complex by dissolving water and mixing with equimolar copper(II) acetate. The pH was raised to neutrality with sodium hydroxide. The solution was centrifuged at 20,000 X g for 1 hour at 3°C to remove poorly soluble material. The supernatant solution was lyophilized to obtain glycyl- Lhistidyl-L-lysine n-stearyl esteπcopper(II). By substituting n-palmityl alcohol (or any other alkyl alcohol) for the n-stearyl alcohol, glycyl-Lhistidyl-Llysine n-palmityl ester (or a corresponding alkyl ester) may be synthesized. EXAMPLE 4 SYNTHESIS OF GLYCYLL-fflSΗDYLLLYSINE N-OCTYL AMIDE A solution of N a -t-butyloxycarbonyl-N e -ben._yloxycarbonyl-Llysine in tetrahydrofuran was treated with N-methyl-morpholine, isobutyl chloroformate, and octylamine at -15°C * The resulting fully protected octyl amide was then treated with 50% trifluoroacetic acid in dichloromethane at room temperature, neutralized with saturated aqueous potassium bicarbonate solution, and extracted into ethyl acetate. Evaporation gave the deblocked lysinamide which was added to a solution prepared from N^t-butyloxycarbonyl-N-^-ben∑yloxycarbonyl-L- histidine, N-methylmorpholine, and isobutyl chloroformate in dry tetrahydrofuran at -15°C. The fully protected dipeptide formed above was deblocked by treatment with 50% trifluoroacetic acid in dichloromethane at room temperature followed by neutralization with saturated aqueous potassium bicarbonate. Extraction into ethyl acetate and evaporation gave the partially deblocked dipeptide, which was added to a solution prepared from benzyloxycarbonyl glycine, N-methylmorpholine, and isobutyl chloroformate in dry tetrahydrofuran at -15°C. The resulting protected tripeptide was deblocked by treatment with hydrogen in the presence of 10% palladium on carbon in glacial acetic acid. Filtration and lyophilization gave glycyl-L-histidyl-Llysine n-octyl amide as its triacetate salt. EXAMPLE 5 SYNTHESIS OF GLYCYL-LHISTTDYL-LLYSYLLVALYL LPHENYI ^LANYL-LVALINE Multi-gram quantity of glycyl-Lhistidyl-L-lysyl-Lvalyl-L phenylalanyl-Lvaline was synthesized by standard solution phase method using t- butyloxycarbonyl protecting group for the alpha nitrogen, benzyloxycarbonyl group for side-chain protection and mixed anhydride method for coupling. Briefly stated, L-valine benzyl ester p-toluenesulfonate salt was coupled with t- butyloxycarbonyl-Lphenylalanine using isobutyl chloroformate and N- methylmorpholine as a coupling agent (2 hours at -20°C, then 1 hour at ambient temperature). The t-butyloxycarbonyl protecting group of the dipeptide was then removed by 30% trifluoroacetic acid in dichloromethane at room temperature for 30 minutes. Blocked amino acids (t-butyloxycarbonyl-Lvaline, N a -t- butyloxycarbonyl-N e -benzyloxycarbonyl-Llysine, N a -t-butyloxycarbonyl-N ιm - benzyloxycarbonyl-Lhistidine, benzyloxycarbonylglycine) were added in sequential order, and t-butyloxycarbonyl protecting groups were removed to obtain the desired peptide. The final peptide was completely deprotected using hydrogen gas in acetic acid for 5 days in the presence of 10% Pd-C catalyst. The final peptide was lyophilized from water to obtain the tri-acetate salt. EXAMPLE 6 SYNTHESIS OF L-ALANYL-L-HISTIDYLL-LYSINE N e -benzyloxycarbonyl-Llysine benzyl ester hydrochloride salt was suspended in tetrahydrofuran (THF) and coupled with N a -t-butyloxycarbonyl- N ιm -benzyloxycarbonyl-L-histidine using isobutyl chloroformate and N- methylmorpholine (2 equivalents) in THF. After two hours at -20°C and an additional hour at ambient temperature, the reaction was quenched with 2 N aqueous potassium bicarbonate. The product was extracted into ethyl acetate, washed with 1 M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave benzyl N a -t-butyloxycarbonyl-N im -benzyloxycarbonyl-L-histidyl- N e -benzyloxycarbonyl-Llysinate. The product was dissolved in 30% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporate, forming benzyl N ιm - benzyloxycarbonyl-Lhistidyl-N e -benzyloxycarbonyl-Llysinate. This was dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methyl-morpholine and benzyloxycarbonylalanine were added to form benzyl benzyloxycarbonylalanyl- N ιm -benzyloxycarbonyl-Lhistidyl-N e -benzyloxycarbonyl-Llysinate. This product was then dissolved in acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant alanyl-Lhistidyl-Llysine was lyophilized from water several times to yield the desired tripeptide as a diacetate salt. EXAMPLE 7 SYNTHESIS OF LLYSYLLHISTIDYLGLYCINE N^t-butyloxycarbonyl-ϊtf^-benzyloxycarbonyl-Lhistidine was dissolved in tetrahydrofuran (THF) and neutralized with one equivalent of N- methylmoφholine. It was then coupled with benzyl glycinate p-toluenesulfonate salt using isobutyl chloroformate and N-methylmoφholine. After two hours at - 20°C and an additional hour at ambient temperature, the reaction was quenched with 2 N aqueous potassium bicarbonate. The product was extracted into ethyl acetate, washed with 1 M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave benzyl N a -t-butylo__ycarbonyl-N ιm -benzylθ3-ycarbonyl-Lhistidyl- glycinate. This product was dissolved in anhydrous methanolic hydrogen chloride (saturated at 0°C) for 5 minutes, followed by removal of solvent under reduced pressure, forming benzyl N un -benzyloxycarbonyl-Lhistidyl-glycinate. This was dissolved in tetrahydrofufan, and isobutyl chloroformate, N- methylmoφholine and N a ,N e -dibenzyloxycarbonyl-Llysine were added to form benzyl N a ,N e -diben-tyloxycarbonyl-Llysyl-N ιm -benzyloxycarbonyl-Lhistidyl- glycinate (3 hours at -20°C, the 1 hour at ambient temperature). This product was then dissolved in methanol/acetic acid, 1:1 (v/v), and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant Llysyl-Lhistidyl-glycine was lyophilized from water several times, then purified by liquid chromatography on a C-18 reverse-phase column to yield the desired tripeptide triacetate salt as a foamy white solid. EXAMPLE 8 SYNTHESIS OF LLYSYLL-HISTIDYLGLYCINE AMIDE N a -t-butyloxycarbonyl-N ιm -benzyloxycarbonyl-Lhistidine was dissolved in tetrahydrofuran (THF) and neutralized with one equivalent of N- methylmoφholine. It was then coupled with glycinamide hydrochloride using isobutyl chloroformate and N-methylmoφholine. After two hours at -20°C and an additional hour at ambient temperature, the reaction was quenched with 2 N aqueous potassium bicarbonate. This product was extracted into ethyl acetate, washed with 1 M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave N a -t-butyloxycarbonyl-N im -benzyloxycarbonyl-Lhistidyl-glycine amide. The product was dissolved in anhydrous methanolic hydrogen chloride (saturated at 0°C) for 30 minutes, followed by removal of solvent under reduced pressure, forming N ιm -benzyloxycarbonyl-Lhistidyl-glycine amide. This was dissolved in tetrahydrofuran, and isobutyl chloroformate, N- methylmoφholine and N a -N e -dibenzyloxycarbonyl-Llysine were added to form benzyl N a ,N e -diben^ * loxycarbonyl-Llysyl-N un -benzyloxycarbonyl-Lhistidyl- glycine amide (3 hours at -20°C, then 1 hour at ambient temperature). This product was then dissolved in glacial acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant Llysyl-Lhistidyl-glycine amide was lyophilized from water several times, then purified by liquid chromatography on a C-18 reverse-phase column to yield the desired tripeptide amide as a triacetate salt. EXAMPLE 9 SYNTHESIS OF LLYSYLLHISTIDYLGLYCINE N-OCTYL ESTER Glycine, octyl alcohol, p-toluenesulfonic acid monohydrate, and benzene were refluxed together over a period of 24 hours using a Dean-Stark trap to azeotropically remove the evolved water. After cooling to room temperature and then adding dry ethyl ether, octyl glycinate p-toluenesulfonate was collected by suction filtration. The salt was treated with saturated sodium bicarbonate solution and extracted into dichloromethane. Evaporation gave the free amine, which was redissolved in dry tetrahydrofuran (THF) and added to a stirring solution of N a -t-butyloxycarbonyl-N ιm -benzyloxycarbonyl-Lhistidine, N- methylmoφholine, and isobutyl chloroformate in dry THF at -20°C and an additional hour at ambient temperature, the reaction was quenched with a 2 N 19 aqueous potassium bicarbonate. The product was extracted into ethyl acetate, washed with 1 M citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting fully protected dipeptide ester was treated with 30% trifluoroacetic acid in dichloromethane at ambient temperature for 40 minutes, neutralized with saturated aqueous sodium bicarbonate solution, and extracted into ethyl acetate. Evaporation gave the partially deprotected dipeptide, which was redissolved in dry THF and added to a stirring solution of N a ,N e - dibenzyloxycarbonyl-Llysine, N-methylmoφholine an isobutyl chloroformate in dry THF at -20°C. The formed, fully protected tripeptide ester was totally deprotected by treatment with hydrogen gas in glacial acetic acid at ambient temperature in the presence of 10% Pd-C catalyst. Filtration through a layer of Celite, lyophilization from water, and purification by liquid chromatography on a C-18 reverse-phase column gave the desired tripeptide ester as its triacetate salt. EXAMPLE 10 SYNTHESIS OF LLYSYLL-HISTIDYLGLYCYLL-VALYL LPHENYLALANYLLVALINE Multi-gram quantity of Llysyl-Lhistidyl-glycyl-Lvalyl-L phenylalanyl-Lvaline was synthesized by standard solution phase method using t- butyloxycarbonyl protecting group for the alpha nitrogen, benzyloxycarbonyl group for side-chain protection and mixed anhydride method for coupling. Briefly stated, Lvaline benzyl ester p-toluenesulfonate salt was coupled with t- butyloxycarbonyl-Lphenylalanine using isobutyl chloroformate and N- methylomoφholine as coupling agent (2 hours at -20°C, then 1 hour at ambient temperature). The t-butyloxycarbonyl protecting group of the dipeptide was then removed by 30% trifluoroacetic acid in dichloromethane at room temperature for 30 minutes. Blocked amino acids (t-butyloxycarbonyl-L-valine, t- butyloxycarbonylglycine, N a -t-butyloxycarbonyl-N ιm -benzylθ)_ycarbonyl-L- histidine, N a , N e -dibenzyloxycarbonyl-Llysine) were added in sequential order and t-butyloxycarbonyl protecting groups were removed to obtain the desired peptide. The final peptide was completely deprotected using hydrogen gas in glacial acetic acid for five days in the presence of 10% Pd-C catalyst. The final peptide was lyophilized from water and purified by liquid chromatography on a C- 18 reverse phase column to produce the desired hexapeptide in multi-gram quantity. The above systematic synthesis proved advantageous over some of the solid phase methods in providing multi-gram quantity of the desired peptide in high purity with minimal purification. EXAMPLE 11 SYNTHESIS OF GLYCYLLHISTTDYLLCAPROLACTAM ^)-3-amino-e-caprolactam was dissolved in tetrahydrofuran (THF) then coupled with N^t-butyloxycarbonyl-N-^-benzyloj ycarbonyl-Lhistidine using isobutyl chloroformate and N-methylmoφholine in THF. After two hours at -20°C and an additional hour at ambient temperature, the reaction was quenched with 2 N aqueous potassium bicarbonate. This produce was extracted into ethyl acetate, washed with 1 M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave N a -t-butyloxycarbonyl-N ιm -benxyloxycarbonyl-L-histidyl-L- caprolactam. The above protected dipeptide was dissolved in 30% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporated, forming N ιm - benzyloxycarbonyl-Lhistidyl-Lcaprolactam. This was then dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methylmoφholine and benzyloxycarbonylglycine were added to form benzyloxycarbonylglycyl-N ιm - benzyloxycarbonyl-L-histidyl-Lcaprolactam. This product was recrystallized once from ethyl acetate then dissolved in acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant glycyl-IΛiistidyl-Lcaprolactam was lyophilized from water several times, then purified by liquid chromatography on a C-18 reverse-phase column to yield the desired tripeptide as a diacetate salt. EXAMPLE 12 SYNTHESIS OF LHISTIDYLGLYCYLLLYSINE N e -benxyloxycarbonyl-Llysine benzyl ester hydrochloride salt was suspended in tetrahydrofuran (THF) and coupled with N a -t-butyloxycarbonyl- glycine using isobutyl chloroformate and N-methylmoφholine in THF. After two hours at -20°C and an additional hour at ambient temperature, the reaction was quenched with 2 N aqueous potassium bicarbonate. The produce was extracted into ethyl acetate, washed with 1 M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave benzyl N a -t-butyloxycarbonyl-glycyl-N e - benzyloxycarbonyl-L-lysinate. The product was dissolved in 30% trifluoroacetic acid in dichloromethane for 30 minutes, then evaporated, forming benzyl glycyl-N e - benzyloxycarbonyl-Llysinate. This was dissolved in tetrahydrofuran, and isobutyl chloroformate, N-methylmoφholine and N a -benzyloxycarbonyl-N ιm - benzyloxycarbonyl-Lhistidine were added to form benzyl N a -benzyloxycarbonyl- N ιm -benzyloxycarbonyl-Lhistidyl-glycyl-N e -benzyloxycarbonyl-Llysinate. This product was then dissolved in acetic acid and hydrogenated overnight in the presence of 10% Pd-C catalyst. The resultant Lhistidyl-glycyl-Llysine was lyophilized from water several times to yield the desired tripeptide as a diacetate salt. EXAMPLE 13 SYNTHESIS OF LHISTIDYLGLYCYLLLYSYL-LPHENYLALANINE To a stirred solution of N-α-BOC-N-e-CBZ-lysine (19.0 g, 50.0 mmol) and N-methylmoφholine (11.5 mL, 10.6 g, 105.0 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (6.8 mL, 7.2 g, 52.5 mmol). After 2 min. phenylalanine benzyl ester tosylate (21.3 g, 50.0 mmol) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 28.25 g (91%) of the blocked dipeptide as a white solid (Ry = 0.94, 10% methanol/dichloromethane), which was used in the following transformation without further purification. A solution of the above t-butyloxycarbonyl protected dipeptide (25.8 g, 41.7 mmol) in 35% trifluoracetic acid/dichloromethane (300 mL) was stirred for 1/2 h at room temperature. The resulting solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate. The product was extracted into ethyl acetate (3 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 31.0 g (ca. 100% + entrained solvent)) of the free-amino compound as a white semi-solid ( R = 0.45, 10% methanol/dichloromethane). To a stirred solution of N-α-BOC-glycine (8.76 g, 50.0 mmol) and N- methylmoφholine (6.0 mL, 5.6 g, 55.0 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (6.8 mL, 7.2 g, 52.5 mmol). After 2 min. a solution of the protected dipeptide (21.6 g, 41.7 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 31.40 g (ca. 100%) of the blocked tripeptide as a white solid (R = 0.66, 10% methanol/dichloromethane), which was used in the following transformation without further purification. A solution of the t-butyloxycarbonyl protected tripeptide (28.1 g, 41.7 mmol) in 35% trifluoracetic acid/dichloromethane (300 mL) was stirred 1/2 h at room temperature. The resulting solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate. The product was extracted into ethyl acetate (3 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 43.1 g (ca. 100% + entrained solvent) of the free amino compound as a white solid (R/ = 0.26, 10% methanol/dichloromethane). To a stirred solution of L(di-CBZ)histidine (21.2 g, 50.0 mmol) and N-methylmoφholine (6.0 mL, 5.6 g, 55.0 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (6.8 mL, 7.2 g, 52.5 mmol). After 2 min. a solution of the protected tripeptide (23.9 g, 41.7 mmol) in 1:1 tetrahydrofuran/dimethylformamide (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2 M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 36.47 g (89%) of the blocked tetrapeptide as a white solid (R * = 0.78, 10% methanol/dichloromethane), which was used in the following transformation after flash chromatography on silica (3% methanol/dichloromethane). To a suspension of the blocked tetrapeptide (10.1 g, 10.3 mmol) in ethanol (250 mL) was added water, until the mixture became very turbid (about 125 mL). The resulting mixture was shaken with palladium chloride (1.83 g, 10.3 mmol) under an atmosphere of hydrogen (5 atm) for 1 h. The reaction mixture became clear within about 1/2 h. The catalyst was removed by filtration and the filtrate was evaporated to give 4.12 g of white semi-solid. This material was dissolved in water, filtered through a 0.2 μ nylon filter, and lyophilized to give 3.87 g (67%) of the desired tetrapeptide dihydrochloride. EXAMPLE 14 SYNTHESIS OF LHISTIDY GLYCYLL-LYSYLLTRYPTOPHAN To a stirred solution of N-α-BOC-N-c-CBZ-lysine (7.0 g, 18.5 mmol) and N-methylmoφholine (4.3 mL, 3.9 g, 38.9 mmol) in tetrahydrofuran (50 mL) at -15°C was added isobutyl chloroformate (2.5 mL, 2.7 g, 19.4 mmol). After 2 min. tryptophan benzyl ester hydrochloride (6.1 g, 18.5 mmol) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 12.25 g (100%) of the blocked dipeptide as a white solid (Ry = 0.80, 10% methanol/dichloromethane), which was used in the following transformation without further purification. A solution of this t-butyloxycarbonyl protected dipeptide (25.8 g, 41.7 mmol) in 35% trifluoracetic acid/dichloromethane (150 mL) was stirred for 1/2 h at room temperature. The resulting solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate. The product was extracted into ethyl acetate (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 11.75 g (ca. 100% + entrained solvent) of the free-amino compound as a white semi-solid. To a stirred solution of N-α-BOC-glycine (3.24 g, 18.5 mmol) and N- methylmoφholine (2.2 mL, 2.1 g, 20.4 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (2.5 mL, 2.7 g, 19.4 mmol). After 2 min. a solution of the protected dipeptide (10.3 g, 18.5 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate, The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfale, filtered, and evaporated to give 14.11 g (ca. 100%) of the blocked tripeptide as a white solid (Ry = 0.60, 10% methanol/dichloromethane), which was used in the following transformation without further purification. A solution of the t-butyloxycarbonyl protected tripeptide (13.1 g, 18.5 mmol) in 35% trifluoracetic acid/dichloromethane (150 mL) was stirred 1/2 h at room temperature. The resulting dark puφle solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate, fully discharging the color. The product was extracted into ethyl acetate (3 x 100 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 14.7 g (ca. 100% + entrained solvent) of the free amino compound as a foamy semi-solid (R = 0.20, 10% methanol/dichloromethane). To a stirred solution of L(di-CBZ)histidine (7.8 g, 18.5 mmol) and N-methylmoφholine (2.2 mL, 2.1 g, 20.4 mmol) in tetrahydrofuran (50 mL) at -15°C was added isobutyl chloroformate (2.5 mL, 2.7 g, 19.4 mmol). After 2 min. a solution of the protected tripeptide (11.3 g, 18.5 mmol) in THF (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with 1M citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 15.8 g (84%) of the blocked tetrapeptide as a yellow semi-solid (R = 0.85, 10% methanol/dichloromethane), which was used in the following transformation after flash chromatography on silica (4% methanol/dichloromethane). To a suspension of the blocked tetrapeptide (7.6 g, 7.5 mmol) in ethanol (120 mL) was added water, until the mixture became very turbid. The resulting mixture was shaken with palladium chloride (1.33 g, 7.5 mmol) under an atmosphere of hydrogen (5 atm) for 18 h. The catalyst was removed by filtration and the filtrate was evaporated to give a white semi-solid. This material was dissolved in water, filtered through a 0.2 μ nylon filter, and lyophilized to give 2.85 g (64%) of the desired tetrapeptide dihydrochloride as a white powder: [α] D -21.9°(c 2, water). EXAMPLE 15 SYNTHESIS OF LHISΗDYL-L-LYSYL-L-PHENYLALANINE To a stirred solution of N-α-BOC-N-e-CBZ-lysine (9.5 g, 25.0 mmol) and N-methylmoφholine (3.0 mL, 2.8 g, 27.5 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (3.4 mL, 3.6 g, 26.3 mmol). After 2 min. a solution of phenylalanine benzyl ester tosylate (10.7 g, 25.0 mmol) and N- methylmoφholine (2.9 mL, 2.6 g, 26.0 mmol) in dimethylformamide (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with IM citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 15.5 g (100%) of the blocked dipeptide as a white solid (R/ = 0.72, 10% methanol/dichloromethane), which was used in the following transformation without further purification. A solution of this t-butyloxycarbonyl protected dipeptide (15.4 g, 25.0 mmol) in 35% trifluoracetic a d/dichloromethane (150 mL) was stirred for 1/2 h at room temperature. The resulting solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate. The product was extracted into ethyl acetate (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 15.2 g (ca. 100% + entrained solvent) of the free-amino compound as a white semi-solid (R = 0.45, 10% methanol/dichloromethane). To a stirred solution of L(di-CBZ)histidine (11.0 g, 26.0 mmol) and N-methylmoφholine (3.1 mL, 2.9 g, 28.6 mmol) in tetrahydrofuran (100 mL) at -15°C was added isobutyl chloroformate (3.5 mL, 3.7 g, 27.3 mmol). After 2 min. a solution of the protected tripeptide (12.9 g, 25.0 mmol) in tetrahydrofuran (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with IM citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 22.4 g (97%) of the blocked tetrapeptide as a white solid (Ry = 0.78, 10% methanol/dichloromethane). To a suspension of the blocked tetrapeptide (22.3 g, 24.1 mmol) in ethanol (200 mL) was added water, until the mixture became very turbid (about 200 mL). The resulting mixture was shaken with palladium chloride (4.43 g, 25.0 mmol) under an atmosphere of hydrogen (5 atm) for 18 h. The catalyst was removed by filtration through Celite ® - and the filtrate was evaporated to give a white semi-solid. This material was dissolved in water, filtered through a 0.2 μ nylon filter, and lyophilized to give %_._. g (100%) of the desired tetrapeptide dihydrochloride as a fluffy white powder: [α]-ø 3.26° (c 2, water). EXAMPLE 16 SYNTHESIS OF LfflSTIDYL-LPHENYLALANYL-LLYSINE To a stirred solution of N-α-BOC-Lphenylalanine (7.3 g, 25.7 mmol) and N-methylmoφholine (3.3 ml_, 3.1 g, 30.2 mmol) in tetrahydrofuran (50 mL) at -15°C was added isobutyl chloroformate (3.8 mL, 4.0 g, 28.9 mmol). After 2 min. a solution of L(-N-e-CBZ)lysine benzyl ester hydrochloride (10.2 g, 25.0 mmol) and N-methylmoφholine (2.9 mL, 2.6 g, 26.0 mmol) in dimethylformamide (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with IM citric acid (3 x 100 mL), water, 2M KHCO3 (3 x 100 mL), water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 15.5 g (100%) of the blocked dipeptide as a white solid (Ry = 0.92, 10% methanol/dichloromethane). A solution of this t-butyloxycarbonyl protected dipeptide (15.4 g, 25.0 mmol) in 35% trifluoracetic acid/dichloromethane (150 mL) was stirred for 1/2 h at room temperature. The resulting solution was concentrated in vacuo and neutralized with 2M aqueous potassium bicarbonate. The product was extracted into ethyl acetate (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to give 9.5 g (73%) of the free-amino compound as a white semi-solid (R = 0.55, 10% methanol/dichloromethane). To a stirred solution of L(di-CBZ)histidine (8.47 g, 20.0 mmol) and N-methylmoφholine (2.4 mL, 2.2 g, 22.0 mmol) in tetrahydrofuran (50 mL) at -15°C was added isobutyl chloroformate (2.7 mL, 2.9 g, 21.0 mmol). After 2 min. a solution of the protected tripeptide (9.5 g, 18.3 mmol) in tetrahydrofuran (50 mL) was added. The reaction mixture was stirred at -15°C for 1.5 h and then allowed to warm to 0°C. At this time the reaction was quenched by the addition of 2M aqueous potassium bicarbonate. The products were extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with IM citric acid (3 x 100 mL), water, 2M KHCO3 ( 3 10 ° mL ). water, and brine. The resulting solution was dried over sodium sulfate, filtered, and evaporated to give 15.7 g (86%) of the blocked tripeptide as a white solid (R/ * = 0.71, 10% methanol/dichloromethane). To a suspension of the blocked tripeptide (15.0 g, 16.3 mmol) in isopropynol (175 mL) was added water, until the mixture became very turbid (about 175 mL). The resulting mixture was shaken with palladium chloride (2.93 g, 16.3 mmol) under an atmosphere of hydrogen (5 atm) for 18 h. The catalyst was removed by filtration through Celite ® and the filtrate was evaporated to give 7.54 g of a white solid. This material was dissolved in water, filtered through a 0.2 μ nylon filter, and lyophilized to give 7.84 g (96%) of the desired tripeptide dihydrochloride as a white powder: [αjp 10.4° (c 2, water). EXAMPLE 17 SUPEROXIDE DISMUTASE MIMETIC ACTIVITY OF HYDROPHOBIC METAL:PEPTTDE COMPLEXES Metakpeptide complexes of the present invention which contain long chain aliphatic esters or other functional groups which alter the hydrophobic nature of the peptide possess unexpectedly high SOD activity when compared to glycyl-L-histidyl-Llysine:copper(II) ("GHLCu"). Peptides which posses SOD activity are termed "SOD mimetics." In this example, superoxide dismutase mimetic activity was measured by the xanthine oxidase/NBT method (Oberley and Spitz, Handbook of Methods for Oxygen Radical Research, R. Greenwald ed., pp. 217-220, 1985; Auclair and Voisin, Handbook of Methods for Oxygen Radical Research, R. Greenwald ed., pp. 123-132, 1985). The reactions contained the following: 100 uM xanthine, 56 uM NBT (nitro blue tetrazolium) 1 unit of catalase, and 50 mM potassium phosphate buffer, pH 7.8. The reaction was initiated by the addition of xanthine oxidase in sufficient quantity to obtain an increase in absorbance at 560 nm of approximately 0.025/min. in a total sample volume of 1.7 ml. The xanthine oxidase was prepared fresh daily and stored on ice until used. All the components of the reaction are added except the xanthine oxidase and the spectrophotometer was adjusted to zero at 560 nm. The reaction was initiated by the addition of the xanthine oxidase. All reagents were obtained from Sigma Chemical Co. Measurements of the absorbance at 560 nm were taken at 1-2 minute intervals for at least 16 minutes following addition of xanthine oxidase. A control consisted of reactions containing no metakpeptide complex. One unit of SOD activity was taken as that amount of sample in micromoles which inhibits the control reaction with the NBT by 50%. The relative activity is obtained by comparing the micromoles of metakpeptide complex necessary to produce a 50% inhibition of the control reactions. The - *i f lower the value, the more active the compound is as a SOD mimetic. GHLCu is included in all experiments to serve as a positive control (i.e., a complex known to possess SOD mimetic activity). The inclusion of GHL-Cu permits comparison of all complexes tested relative to the activity exhibited by GHLCu. All complexes were tested at a 2:1 molar ratio of peptide to metal. The results of this experiment are summarized in Table 1. It should be noted that the absolute value found in enzymatic assays for SOD mimetic activity varries depending upon the enzyme lot used in the evaluation. Thus, the inclusion of GHLCu permits comparisons from experiment to experiment based on a normalized activity relative to GHL-Cu. TABLE 1 EFFECT OF HYDROPHYLIC MODIFICATIONS ON SOD MIMETIC ACTIVITY GHL:Cu = glycyl-L-histidyl-L-lysine:copper(II) GHL-Octyl EsteπCu = glycyl-L-histidyl-L-lysine n-octyl estencopper(II) GHLVFV:Cu = glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GHLAFA:Cu = gly ( yl-I_^histidyl-L-lysyl-L-alanyl-I_ ^ phenylalanyl-L-al-_Qine:copper(II) GHL-Palmityl EsteπCu = glycyl-L-histidyl-L-lysine n-palmityl ester:copper(II) LHG-Octyl EsteπCu _= lysyl-L-histidyl-L-glycine n-octyl esteπcopper(II) LHGVFV:Cu = lysyl-L-histidyl-glycyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GHL-Octyl Amide:Cu = gtycyl-L-histidyl-L-lysine n-octyl amide:copper(II) EXAMPLE 18 SUPEROXIDE DISMUTASE MIMETIC ACTIVITY OF METAL:PEPTIDE COMPLEXES Metakpeptide complexes of the present invention containing modifications in the amino acid sequence or other modifications to individual amino acid components possess unexpectedly high SOD activity when compared to GHLCu. In this example, superoxide dismutase was measured by the xanthine oxidase/NBT method as described in Example 17. Each complex was tested relative to GHLCu assayed at the same time. All complexes were tested at a 2:1 molar ratio of peptide to metal. The results of the this experiment are summarized in Table 2. TABLE 2 EFFECT OF SEQUENCE AND AMINO ACID MODIFICATION ON SOD MIMETIC ACTIVITY G(3-Methyl)HL:Cu = gly(yl-L-(3-me-hyl)--_is-idyl-L-lysine:copper(II) GHCadaverine:Cu = glycyl-L-histidyl-cadaverine:copper(II) G(3-Methyl)HLVFV:Cu = glyc * yl-L-(3-methyl)-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) GLH:Cu = glycyl-L-lysyl-L-hist_dine:copper(II) LHG-Amide:Cu = lysyI-L-histidyl-L-glycine amide:copper(II) AHL:Cu = alanyl-L-__istidyl-L-lysine:copper(II) GHCaprolactam:Cu = lysyl-L-histidyl-caprolactam:copper(II) HGL:Cu = L-histidy_-glycyl-L-lysine:copper(II) HGLF:Cu = L-histidyl-glycyl-L-lys e-L-phenylalanine:copper(II) HFL:Cu = L-histidyl-L-phenylalanyl-L-lysme:copper(II) HLF:Cu = L-histidyl-L-l j «yl-I_-phenylalanine:coρper(II) EXAMPLE 19 SUPEROXIDE DISMUTASE MIMETIC ACTIVITY OF METAL:PEPTIDE COMPLEXES Substitution of other metal ions copper(II) in the metakpeptide complex gives complexes with high SOD activity when compared to GHLCu. In this example, superoxide dismutase was measured by the xanthine oxidase/NBT method as described in Example 17. Each compoimd was tested relative to GHLCu assayed at the same time. All complexes were tested at a 2:1 molar ratio of peptide to metal. The results of the this experiment are summarized in Table 3. TABLE 3 EFFECT OF METAL ION ON SOD MIMETIC ACnVITY NOTES TO TABLE 3. GHL:Cu = glycyl-L-histidyl-L-lysine:copper(II) GHL:Mn = glycyl-L-histidyl-L_lysine:manganese(II) GHL-Octyl:Cu = glycyl-L-histidyl-L-lysine n-octyl esteπcopper(II) GHL-Octyl:Mn = g_ycy_-I_-histidyl_L-lysine n-octyl ester:manganese(II) HGL:Mn = L-histidyl-glycyl_L_lysine:manganese(II) GLH:Mn = glycyl-L-lysyl-L-histidine:manganese(ϋ) AHL:Mn = alanyl-L-histidyl-L-lysine:manganese(II) EXAMPLE 20 SUPEROXIDE DISMUTASE MIMETIC ACTIVITY OF METALPEFΠDE COMPLEXES The metakpeptide complexes of the present invention may be modified with the addition of a chelating agent to the metakpeptide complex to yield a ternary metal:peptide:chelating agent complex with enhanced SOD mimetic activity when compared to GHLCu. As mentioned previously, to form such a ternary complex, the molar ratio of metal to peptide to chelating agent must be considered. For example, if the ratio of peptide to metal is 2:1, the addition of a chelating agent to the metakpeptide complex is difficult due to site occupancy by the peptide. However, by keeping the ratio of metal to peptide near 1:1 a chelating agent may be may be added. In this example, superoxide dismutase was measured by the xanthine oxidase/NBT method as described in Example 17. Each compound was tested relative to GHL-Cu or glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl- valine:copper(II) ("GHLVFV-Cu") assayed at the same time. In this example, the amount of complex for 50% inhibition is expressed as ug copper(II) added per reaction necessary to achieve 50% inhibition of the control reaction. The results of this experiment are summarized in Table 4. TABLE 4 EFFECT OF ADDITIONAL CHELATION GROUPS ON SOD MIMETIC ACTIVITY GHL:Cu:Im = glycyl-L-histidyl-L-lysine:copper(π):imidazole GHLVFVrCu = gJycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-va_ine:copper(II) GHLVFV:Cu:H = glycyl-I_-__istidyl-L-lysyl-I_ ^ valyl-L_phenylalanyl-L-valine:copper(II):histidine GHLVFV:Cu:Im = glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II):imidazole EXAMPLE 21 SUPEROXIDE DISMUTASE MIMETIC ACTIVITY OF META PEPTIDE COMPLEXES CONTAINING ALBUMIN BINDING MOIETIES Metakpeptide complexes of the present invention containing tryptophan demonstrate enhanced SOD mimetic activity relative to the GHL-Cu. In this example, superoxide dismutase was measured by the xanthine oxidase/NBT method as described in Example 17. Each compound was tested relative to GHLCu assayed at the same time. The results of this experiment are summarized in Table 5. TABLE 5 EFFECT ON SOD MIMETIC ACTIVITY BY ALBUMIN BINDING MOIETIES COMPOUND RATIO CONC. FOR RELATIVE 50% INHIB. to (umoles/ml) GHLCu glycyl_L-histidyl_L-lysine:copper(II) G(3-Methyl)HLGW:Cu = glycyl-L-(3-methyl)-histidyl-L-lysyl-glycyl-L-tryptophan:copper(II) GHLW.Cu = glycyl-L-l-istidyl-L-lysyl-L-tryptophanxopper^) EXAMPLE 22 INHIBΓΠON OF FERRΓΠN IRON RELEASE BY META PEPTIDE COMPLEXES Iron metabolism is involved in lipid peroxidation. One of the mechanisms for this is the release of iron, Fe(lTI)/Fe(II), from ferritin, the major storage site of iron in the body, and subsequent participation of the free Fe(πi)/Fe(π) in lipid peroxidation reactions. Iron release from ferritin is dependent on the generation of superoxide anion in the reactions. In an animal, superoxide anion is generated at the site of a wound or chronic inflammation by host defense mechanisms such as the neutrophils. The metakpeptide complexes of the present invention inhibit the release of Fe(III)/Fe(II) from ferritin. Iron release from ferritin was measured by incubating ferritin with 10 um of a metakpeptide complexes of the present invention and deterrnining the amount of iron released. Reaction mixtures contained 0.33 mM xanthine, 25 mU/ml xanthine oxidase, and 90 U/ml catalase as described in Example 17. In addition, 200 uM ferritin was added as a source of iron and 150 uM bathophenanthroline disulfonate to chelate and released iron. The release of iron was measured as an increase in the absoφtion of 535nm due to the iron- bathophenanthroline complex. The data is presented in Table 6 as this absoφtion rate and as a percent inhibition of a reaction with no additions. All the metakpeptide complexes are at a molar ratio of peptide to metal of 1:1. TABLE 6 INHIBITION OF FERRITIN IRON RELEASE BY METALPEPTIDE COMPLEXES GHLVFV:Cu = glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-valine:copper(II) G(3-Methyl)HL:Cu = glycyl-L-(3-methyl)-__istidyl-L-lysine:copper(II) HGL:Cu = L-histidyl-gfycyl-L_lysine:copper(II) EXAMPLE 23 INHIBITION OF FERRTTIN AND SUPEROXIDE ANION DEPENDENT LIPID PEROXIDATION BY METALPEPTIDE COMPLEXES The iron released from ferritin can participate in lipid peroxidation reactions. Metakpeptide complexes of the present invention inhibit the lipid peroxidation mediated by the release of Fe(m)/Fe(II) from ferritin. Lipid peroxidation was measured by determining the oxidation of lipids in liposomes prepared from rat liver lipids. Incubations were as described in Example 22 except that rat liver lipid microsomes were included. The oxidation was followed by determining the amount of malondialdehyde ("MDA") formed 5 during the reaction. The data is presented in Table 7 as this absoφtion rate and as a percent inhibition of a reaction with no additions. All the metakpeptide complexes are at a molar ratio of peptide to metal of 1:1. TABLE 7 l o INHIBITION OF SUPEROXIDE AND FERRITIN DEPENDENT LIPID PEROXIDATION BY METAL.PEPTIDE COMPLEXES COMPOUND RATE PERCENT 15 nmole MDA/min/ml INHIBITION GHL:Cu = glycyl-L-histidyl-L_lysine:copper(II) 30 GHL Octyl EsteπCu = glycyl-L-histidyl-L-lysine n-octyl esteπcopper(II) GHLVFV.Cu = 35 glycyl-L-histidyl-L-lysyl-L-valyl-L-phenylalanyl-L-vaIine:copper(II) G(3-Methyl)HL:Cu = glycyl-L-(3-methyl)-histidyl-L-lysine:copper(II) 0 HGL:Cu = L-histidyl-glycyl-L-lysine:copper(II) From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for puφoses of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not to be limited except as by the appended claims.

Claims: Claims 1. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [glycyl-L-histidyl-Llysine-R]:metal wherein R is an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L- tryptophan, (glycyl)y-Ltryptophan, where y = 1-4, Lprolyl-Xι-Lphenylalanyl-X2 or Xl-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L- valine, L-alanine and glycine, and where Xi and X2 are not both Lvaline, (X3) n -L- tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 2. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [glycyl-R -R2-R3]:metal wherein R is selected from the group consisting of L-histidyl, L-(3-W)-histidyl and L-(5-W)-histidyl, where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R 2 is -NHCH((CH 2 )nNH3 + )CO- where n = 5-10; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-Ltryptophan, where y = 1-4, L-prolyl-Xi-L-phenylalanyl- X2 or Xι-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, L-alanine and glycine, and where Xi and X2 are not both L-valine, (X3) n - L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper (II) or manganese(II). 3. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [glycyl-Rι-R2-R3]:metal wherein Rl is selected from the group consisting of L(3-W)-histidyl and L-(5-W)- histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is L-lysyl; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is Ltryptophan, (glycyl)y-Ltιyptophan, where y = 1-4, Lprolyl-Xi-Lphenylalanyl- X2 or X -Lphenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, Lalanine and glycine, and whete Xi and X2 are not both Lvaline, (X3) n - Ltryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 4. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [glycyl-Rι-R2-R3]:metal wherein R is selected from the group consisting of histidyl, (3-W)-histidyl and L(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is a basic amino acid, a basic amino moiety, or a modified basic amino acid; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6-12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is Ltryptophan, (glycyl)y-Ltryptophan, where y = 1-4, L-prolyl-Xι-Lphenylalanyl-X2 or Xi-L- phenylalanyl-X2, where Xi and X2 are selected from the group consisting of Lvaline, Lalamne and glycine, (X3) n -Ltryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 5. A metakpeptide complex possessing ' anti-oxidative and anti- inflammatory activity, said complex having the general formula: [Rl-R2-glycine-R3]:metal wherein Rl is Llysyl or -NHCH((CH 2 )nNH 3 + )CO- where n = 5-10; R2 is selected from the group consisting of L-histidyl, L-(3-W)-histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6-12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is Ltryptophan, (glycyl)y-Ltryptophan, where y = 1-4, Lprolyl-Xι-L-phenylalanyl-X2 or Xi-L- ρhenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, Lalanine and glycine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 6. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [Rl-R2-R3-R4J:metal wherein Rl is Llysyl or -NHCH((CH2) n NH3 + )CO- where n = 5-10; R2 is selected from the group consisting of Lhistidyl, L(3-W)-histidyl and L(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is a basic amino acid, a basic amino moiety, or a modified basic amino acid; R4 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6-12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-Ltryptophan, where y = 1-4, L-prolyl-Xι-Lphenylalanyl-X2 or Xi-L- phenylalanyl-X2, where Xi and X2 are selected from the group consisting of L-valine, Lalanine and glycine, (X3) n -Ltτyptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 7. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [Rl-glycyl-R 2 -R3]:metal wherein Rl is selected from the group consisting of Lhistidyl, L-(3-W)-histidyl and L(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R2 is Llysyl, -NHCH((CH2) n NH3 + )CO-, where n = 5-10, or a basic amino acid, a basic amino moiety, or a modified basic amino acid; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety contaimng from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6-12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is Ltryptophan, (glycyl)y-Ltryptophan, where y = 1-4, Lprolyl-Xι-Lphenylalanyl-X2 or Xi-L- phenylalanyl-X2, where Xi and X2 are selected from the group consisting of Lvaline, Lalanine and glycine, (X3) π -Ltryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 8. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [Lalanyl-R 1 -R2-R3] metal wherein R is selected from the group consisting of Lhistidyl, L(3-W)-histidyl and L(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R 2 is Llysyl or -NHCH((CH 2 ) n NH 3 + )CO- where n = 5-10; R3 is -NH2, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-Ltryptophan, where y - 1-4, prolyl-Xi-Lphenylalanyl- X2 or Xι-L-phenylalanyl-X2, where Xi and X2 are selected from the group consisting of Lvaline, L-alanine and glycine, and where Xi and X2 are not both Lvaline, (X3) n - Ltryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 9. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [glycyl-Rι-R2-R3] :metal wherein Rl is Llysyl or -NHCH((CH2) n NH3 + )CO- where n = 5-10 R2 is selected from the group consisting of Lhistidyl, L(3-W)-histidyl and L-(5-W)-histidyl where W is an alkyl moiety containing from 1 to 12 carbons atoms or aryl moiety containing from 6-12 carbon atoms; R3 is hydrogen, -NH2, an alkyl moiety containing from 1 to 18 carbon atoms, an aryl moiety containing from 6 to 12 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, an aryloxy moiety containing from 6-12 carbon atoms, an aminoalkyl moiety containing from 1 to 18 carbon atoms, or is L-tryptophan, (glycyl)y-L-tryptophan, where y = 1-4, Lprolyl-Xι-Lphenylalanyl-X2 or Xi-L- phenylalanyl-X2, where Xi and X2 are selected from the group consisting of Lvaline, Lalanine and glycine, (X3) n -L-tryptophan, where X3 is a -CH2- or -CH(OH)- moiety and n = 4-20, or -(X4) n , where X4 is a naturally occurring carbohydrate selected from the group consisting of glucose, mannose, galactose, glucosamine and galactosamine and n = 1-5; and metal is copper(II) or manganese(II). 10. A metakpeptide complex possessing anti-oxidative and anti- inflammatory activity, said complex having the general formula: [Rl-R2-R3]:metal wherein Rl is selected from the group consisting of Lhistidyl, L-(3-W)-histidyl and L-(5-W)-histidyl, where W is an alkyl moiety containing from 1 to 12 carbons atoms or an aryl moiety containing from 6-12 carbon atoms; R2 is selected from the group consisting of L-lysyl, a basic amino acid, a hydrophobic amino acid, and -NHCH((CH2) n NH3 + )CO- where n = 5-10; R3 is selected from the group consisting of Llysyl, a basic amino acid, a hydrophobic amino acid, -NHCH((CH2) π NH3 + )CO- where n = 5-10, an amino moiety, and a modified amino acid; and metal is copper(II) or manganese(II). 11. The metakpeptide complex of any one of claims 1-10, wherein the ratio of peptide to metal is 2:1. 12. The metakpeptide complex of any one of claims 1-10, further including a pharmaceutically acceptable carrier or diluent. 13. The metakpeptide complex of any one of claims 1-10, further including a chelating agent such that a ternary metakpeptide:chelating agent complex is formed, the chelating agent being imidazole or an imidazole-containing compound. 14. The metakpeptide complex of claim 13 wherein the imidazole- containing compound is histidine. 15. The metakpeptide complex of any one of claims 1-10, further including a chelating agent such that a ternary metal:peptide:chelating agent complex is formed, the chelating agent being cysteine or methionine. 16. A composition for use as an active therapeutic substance comprising a metakpeptide complex of any one of claims 1-10 and a pharmaceutically acceptable carrier or diluent. 17. A compound for use in the manufacture of a medicament for enhancing or restoring the resistance of a warm-blooded animal to oxidative or inflammatory damage caused by release of reactive oxygen species, the compound being a metakpeptide complex of any one of claims 1-10.

Inventors: PICKART LOREN R, PICKART, LOREN, R.
Applicants: PROCYTE CORP, PROCYTE CORPORATION
Application year: 1991
Main classification: C07K5
IPC codes: A61K38, A61P29, C07K5, C07K7