US20070287662A1 - Multi-component antioxidant compounds, pharmaceutical compositions containing same and their use for reducing or preventing oxidative stress - Google Patents

Multi-component antioxidant compounds, pharmaceutical compositions containing same and their use for reducing or preventing oxidative stress Download PDF

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US20070287662A1
US20070287662A1 US11/797,590 US79759007A US2007287662A1 US 20070287662 A1 US20070287662 A1 US 20070287662A1 US 79759007 A US79759007 A US 79759007A US 2007287662 A1 US2007287662 A1 US 2007287662A1
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hydrophobic
charged moiety
bond
antioxidant
antioxidant compound
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Daphne Atlas
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Yissum Research Development Co of Hebrew University of Jerusalem
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Priority to US13/086,429 priority patent/US20110190195A1/en
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    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
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Definitions

  • the present invention relates to antioxidant compounds, pharmaceutical compositions containing same and their use for preventing or reducing oxidative stress. More particularly, the present invention relates to novel non-central nervous system (CNS) and CNS targeted antioxidants and their use in treating non-CNS and CNS disorders, diseases or conditions associated with a formation of oxidative stress.
  • CNS central nervous system
  • the cellular physiological reduction-oxidation (redox) state which is dependent on concentrations of oxygen and reactive oxygen species (ROS), is involved in controlling central biochemical regulatory processes, such as tyrosine phosphorylation, regulation of transcription and alteration in messenger RNA stability (1
  • SOD superoxide dismutase
  • SOD superoxide dismutase
  • catalase catalase
  • selective antioxidants such as glutathione.
  • Regulated homeostasis of the intracellular redox state is essential to the proper physiological functioning of the cell, however, overproduction of (ROS), at levels exceeding the neutralization capacity of cellular antioxidant defenses, generates an oxidative state, termed oxidative stress.
  • Inflammation a normal physiological process involving limited tissue injury, can be pathogenic if uncontrolled, as under conditions of excessive oxidative stress.
  • elevation of ROS via alterations in expression of redox state-responsive genes, causes the ubiquination and destruction of the NF- ⁇ B inhibitory proteins, thereby allowing NF- ⁇ B to bind to target gene promoters, a pivotal event in the upregulation of multiple pro-inflammatory cytokines (2
  • An excess of free radicals has been identified in many diseases associated with inflammation, such as sepsis, multiple sclerosis (MS), stroke, myocarditis and rheumatoid arthritis.
  • ROS reactive oxygen species
  • JNK c-Jun N-terminal kinase
  • ROS were shown to play a role as intermediate factors in the pathway of various signal transduction pathways involving thioredoxin, a ubiquitous enzyme in all living cells containing a specific redox-active site.
  • Thioredoxin acts as an inhibitor of oxidative stress induced apoptosis by binding to, and thereby inhibiting, apoptosis signal regulating kinase-1 (ASK1), a protein mediating oxidative stress-induced apoptosis via a redox state responsive domain.
  • ASK1 apoptosis signal regulating kinase-1
  • oxidized thioredoxin dissociates from ASK1, thereby activating it and triggering apoptosis.
  • Oxidant injury has been implicated in the pathology of a wide-ranging variety of diseases, including many of major clinical and economic impact, such as cardiovascular, neurological, metabolic, infectious, hepatic, pancreatic, rheumatoid, malignant and immunological diseases, as well as conditions such as sepsis, cataract, amyotrophic lateral sclerosis and congenital diseases such as Down syndrome, multiple organ dysfunction (7) and cystic fibrosis
  • oxidative stress is an etiological factor.
  • Neurodegenerative pathologies-involvement of inflammation and oxidative stress Evidence has accumulated demonstrating a strong linkage of oxidative stress with pathogenesis of major human neurodegenerative disorders (8-10) including Parkinson's disease (11, 12), Alzheimer's disease (13-15), Creutzfeldt-Jakob disease (16) as well as MS (17).
  • oxidative stress in the pathogenesis of Alzheimer's disease was indicated in a recent analysis of the relationship between ⁇ -amyloid protein fragment and oxygen radical formation.
  • This study employed a highly sensitive system, utilizing monitoring blood vessel vasoactive responses, in which ⁇ -amyloid-mediated enhancement of phenylephrine-mediated vasoconstriction could be abrogated by pretreatment of blood vessels with SOD, an enzyme which scavenges oxygen free radicals (15).
  • SOD se.g., SOD
  • Other studies have shown that oxidative stress and free radical production are linked to the presence of ⁇ -amyloid fragment (amino acids 25-35) and likely contribute to neurodegenerative events associated with Alzheimer's disease (18).
  • Further studies have shown extensive RNA oxidation in neurons in Alzheimer's disease and Down's syndrome (13, 14) and genetic evidence for oxidative stress in Alzheimer's disease has also been reported (19, 20).
  • Cataract formation A role for oxidant injury in cataract formation was shown in early studies demonstrating that decreased levels of the antioxidant hepatic glutathione-5-transferase (GSH) are associated with increasing opacity of the lens (27). Later studies have shown that in the mammalian lens, intracellular oxidants produced by light induced oxidative processes cause oxidative damage, result in changes in gene expression, and are causally related to cataract formation. It is presently believed that H 2 O 2 is the major oxidant to which the lens is exposed (28).
  • GSH hepatic glutathione-5-transferase
  • Infectious diseases Harmful levels of oxygen free radicals and nitric oxide (NO) are generated in a diverse range of, and are essential to, the pathogenesis of many types of microbial infections (29).
  • Viral diseases whose pathogenesis is associated with oxidative stress include hepatitis C, AIDS, influenza and diseases caused by various neurotropic agents.
  • high levels of NO generate highly reactive nitrogen oxide species including reactive oxygen intermediates as well as peroxynitrite, via interaction with oxygen radicals. These species of reactive nitrogen cause oxidant injury as well as mutagenesis via oxidation of various biomolecules.
  • Recent evidence has also demonstrated that oxidative stress induced by NO causes further harm by increasing viral mutation rates and by suppressing type 1 helper T cell function.
  • EIV influenza virus equine influenza virus
  • studies employing the equine influenza virus (EIV) influenza model have shown that viral infection causes cytopathogenic effects and apoptosis as a result of oxidative stress (30).
  • Another study has shown that progression of human hepatitis C virus infection involves triggering of oxidative stress via a mechanism in which the non-structural HCV protein NS5A triggers elevation of ROS in mitochondria, leading to the nuclear translocation and constitutive activation of the pro-inflammatory transcription factors NF- ⁇ B and STAT-3 (31).
  • Neurological dysfunction following cardiac surgery Cardiac operations, such as coronary bypass surgery, following multiple infarctions has been shown to significantly increase the risk of neurologic dysfunction, such as impairment of brain function and memory (32-34). Studies have provided evidence that such neurological impairment is associated with oxidative stress (35).
  • Cardiovascular diseases The pathogenesis of major cardiovascular diseases, such as atherosclerosis, hypertension, stroke and restenosis, has been shown to involve oxidative stress. Such oxidant stress in the vasculature causes adverse vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation (36). In the case of atherosclerosis, one of the leading causes of mortality in the developed world, pathogenesis specifically involves inflammation and oxidation of lipoprotein-derived lipids (37).
  • the pathogenesis of a very broad variety of diseases involves oxidative stress and, as such, methods of reducing oxidative state may provide an attractive means of treating such diseases.
  • BBB blood brain barrier
  • Vitamin E was found to be ineffective at decreasing oxidative stress in the substantia nigra and, although capable of crossing the BBB, is trapped in the cell membrane and therefore does not reach the cytoplasm where its antioxidant properties are needed.
  • Vitamin C was shown to cross the BBB to some extent, via a selective transporter, nevertheless it has also been shown to be ineffective in treating neurodegenerative diseases of the CNS.
  • antioxidant compounds characterized by a combination of low molecular weight and membrane miscibility properties for permitting the compounds to cross the BBB of an organism, a readily oxydizable (i.e., reducing) chemical group for exerting antioxidation properties and a chemical make-up for permitting the compounds or their intracellular derivative to accumulate within the cytoplasm of cells, have been employed to treat pathology, including CNS pathology, associated with oxidative stress (44).
  • the antioxidant NAC has been employed to treat canine kidney cells so as to attenuate EIV-induced cytopathic effect and apoptosis (30) and to treat atherosclerosis and restenosis following angioplasty (46). Dimers of NAC have also been employed for treating atherosclerosis (37).
  • the sulphur-containing fatty acid with antioxidant properties has been employed to achieve long-term reduction of restenosis following balloon angioplasty in porcine coronary arteries (47).
  • the antioxidants pyrrolidine dithiocarbamate (PDTC) and NAC have been used to prevent pathogenic HCV mediated constitutive activation of the pro-inflammatory transcription factor STAT-3 (31).
  • Synthetic antioxidants have also been employed to treat oxidative stress related disease. For example, treatment of asthma has been attempted by reducing the levels of free oxygen using the synthetic reactive oxygen inhibitor 2,4-diaminopyrrolo-2,3-dipyrimidine (48).
  • Apoptosis in an ischemic swine heart model has been treated with ebselen, a glutathione peroxidase mimic (35).
  • the cytosolic antioxidant copper/zinc superoxide dismutase, has been employed to treat blood-brain barrier disruption and infarction following cerebral ischemia-reperfusion (49). Attenuation of ischemia-induced mouse brain injury has been attempted by administration of SAG, a redox-inducible antioxidant protein (50).
  • metabolic regulators of antioxidants Another approach has attempted to employ metabolic regulators of antioxidants to reduce oxidative stress.
  • Hemin an inducer of the oxidative stress induced protein, heme oxygenase-1, has been utilized to inhibit progression of EAE (23).
  • ARDS acute respiratory distress syndrome
  • ROS reactive oxygen species
  • a common feature characterizing all of the above described and other antioxidant compounds is their limited diversity in structure, body distribution, cellular distribution, organelle distribution, and/or antioxidant properties, etc. As such, any given antioxidant may prove useful for some applications, yet less or non-useful for other applications. In some cases, a specific antioxidant may efficiently reduce oxidative stress in some body parts, some cells, or some subcellular structures, yet not in others.
  • an antioxidant compound which is devoid of the above limitations, which compound will by hydrolyzed in vivo to a plurality of different antioxidant species which will act in concert to reduce or prevent oxidative stress in a plurality of tissues, cell types and cellular organelles, so as to combat disease, syndromes and conditions associated with formation of oxidative stress, both in non-CNS and CNS tissues.
  • an antioxidant compound comprising (a) a peptide including at least three amino acid residues of which at least two being cysteine residues, each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage of the at least two peptide bonds by the at least one intracellular peptidase results in generation of a plurality of antioxidant species, each including
  • a pharmaceutical composition for preventing or reducing oxidative stress comprising a pharmaceutically acceptable carrier and, as an active ingredient, an effective amount of an antioxidant compound, the antioxidant compound including: (a) a peptide including at least three amino acid residues of which at least two being a cysteine residues, each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bondd eac being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross
  • the antioxidant compound has a general formula of: A-Y1-Cys-Y2-Cys-Y3-B wherein, Cys is a cysteine residue, A is the first hydrophobic or non-charged moiety; B is the second hydrophobic or non-charged moiety; Y1, Y2 and Y3 are each individually one or more amino acid residues in the range of 0-30 residues, with the provision that Y1, Y2 and Y3 collectively provide for at least two amino acid residues in the peptide.
  • the A is selected from the group consisting of N-acetyl, tert butyl, isopropyl, n-butyl and n-pentyl.
  • the B is selected from the group consisting of amide and ester.
  • cleavage of the first bond and/or the second bond by a cellular hydrolase results in loosing the membrane miscibility.
  • the cleavage of the first bond and/or the second bond by a cellular hydrolase results in formation of additional antioxidant species acting in synergy.
  • first bond and the second bond are each independently an ester or peptide bond.
  • each of the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety is selected from the group consisting of alkyl, aryl, alkene, arene and cholesteril having a backbone of 2-50 carbon atoms.
  • the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to enable the antioxidant compound to cross a blood barrier.
  • the blood barrier is selected from the group consisting of a blood brain barrier, a blood retinal barrier and a blood testis barrier.
  • a method of treating a disease associated with formation of oxidative stress in a subject comprising locally or systemically administering to the subject an antioxidant compound comprising: (a) a peptide including at least three amino acid residues of which at least two being cysteine residues each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage
  • the disease associated with formation of oxidative stress is a central nervous system disease.
  • the central nervous system disease is selected from the group comprising a neurodegenerative disorder, Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, cerebral ischemia, multiple sclerosis, a degenerative disease of the basal ganglia, a motoneuron disease, scrapies, spongiform encephalopathy, a neurological viral disease, a motoneuron disease, post-surgical neurological dysfunction, memory loss and memory impairment.
  • a neurodegenerative disorder Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, cerebral ischemia, multiple sclerosis, a degenerative disease of the basal ganglia, a motoneuron disease, scrapies, spongiform encephalopathy, a neurological viral disease, a motoneuron disease, post-surgical neurological dysfunction, memory loss and memory impairment.
  • the disease associated with formation of oxidative stress is a non-central nervous system disease.
  • the non-central nervous system disease is selected from the group comprising rheumatoid arthritis, cataract, Down syndrome, cystic fibrosis, diabetes, acute respiratory distress syndrome, asthma, post-surgical neurological dysfunction, amyotrophic lateral sclerosis, atherosclerotic cardiovascular disease, hypertension, post-operative restenosis, pathogenic vascular smooth muscle cell proliferation, pathogenic intra-vascular macrophage adhesion, pathogenic platelet activation, pathogenic lipid peroxidation, myocarditis, stroke, multiple organ dysfunction, complication resulting from inflammatory processes, AIDS, cancer, aging, bacterial infection, sepsis; viral disease, AIDS, hepatitis C, influenza and a neurological viral disease.
  • a method of treating a habit associated with formation of oxidative stress in a subject comprising locally or systemically administering to the subject an antioxidant compound comprising: (a) a peptide including at least three amino acid residues of which at least two being cysteine residues each having a readily oxidizable sulfhydryl group for effecting antioxidation; and at least two peptide bonds each being cleavable by at least one intracellular peptidase; and (b) a first hydrophobic or non-charged moiety being attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety being attached to a carboxy terminal of the peptide via a second bond, the first hydrophobic or non-charged moiety and the second hydrophobic or non-charged moiety are selected so as to provide the antioxidant compound with membrane miscibility properties for permitting the antioxidant compound to cross cellular membranes; wherein cleavage
  • the habit associated with formation of oxidative stress is selected from the group comprising aging, smoking, sun tanning, cancer treatment, radiation, cocaine consumption and morphine consumption.
  • the antioxidant compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier adapts the composition for administration by a route selected from the intranasal, transdermal, intradermal, oral, buccal, parenteral, topical, rectal and inhalation route.
  • the carrier provides the antioxidant compound in solution, suspension, emulsion, gel or skin pad.
  • the composition further includes a formulating agent selected from the group consisting of a suspending agent, a stabilizing agent and a dispersing agent.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing novel multifunctional antioxidant compounds which are non-central nervous system and central nervous system targeted antioxidants, N- and/or C-terminal blocked peptide derivatives for the use in treatment of non-central nervous system and central nervous system disorders related to oxidation processes.
  • FIG. 1 shows the HPLC profile of purified N-acetyl cysteine-glycine-proline-cysteine-amid (referred to herein as CB, SEQ ID NO:1)) compound according to the present invention
  • FIG. 2 shows inhibition of JNK and p38 phosphorylation by CB, NOXi and NAC as determined by immunoprecipitation with specific antibodies against phosphorylated JNK and p38 followed by gel electrophoresis;
  • FIG. 3 represents cellular ROS levels as determined using a fluorescence assay in the presence of CB, NOXi and NAC antioxidants.
  • the present invention is of novel non-CNS and CNS targeted antioxidant compounds effective in treating non-CNS and CNS disorders, diseases or conditions associated with the formation of oxidative stress. More specifically, the compounds of the present invention can be used for the treatment of neurodegenerative disorders in which the pathology in the CNS is associated with oxidative stress, and for treatment of non-CNS tissues in conditions associated with overproduction of oxidants. Moreover, the novel compounds of the present invention can also be used for improving cognitive skills such as memory.
  • Antioxidant compounds are used according to the present invention to relieve oxidative stress within cells.
  • a compound which can be used to relieve oxidative stress according to the present invention (i) has a combination of molecular weight and membrane miscibility properties rendering it capable of crossing blood barriers; (ii) includes a readily oxidizable (i.e., reduced) chemical group, such as, but not limited to, a sulfhydryl (—SH) group derived from a cysteine amino acid residue, for exerting its antioxidation properties; and (iii) has a chemical make-up for permitting it or its cellular derivative(s) to accumulate within the cytoplasm of cells.
  • a readily oxidizable chemical group such as, but not limited to, a sulfhydryl (—SH) group derived from a cysteine amino acid residue, for exerting its antioxidation properties
  • —SH sulfhydryl
  • these properties render the compounds of the present invention suitable for treatment of neurodegenerative disorder of the central nervous system, as well as for treating conditions in which non-CNS tissues, such as, but not limited to, the lungs and/or heart, are damaged due to overproduction of oxidants (i.e., reactive oxygen species), which is the case in, for example, acute respiratory distress syndrome, amyotrophic lateral sclerosis, atherosclerotic cardiovascular disease, multiple organ dysfunction, complication resulting from inflammatory processes, AIDS, cancer and aging.
  • oxidants i.e., reactive oxygen species
  • non-CNS tissues refers to all body tissues, such as peripheral central nervous system tissues and non-nervous system tissues, with the exclusion of CNS tissues such as the brain and spinal cord.
  • prior art antioxidant compounds are limited in their structure diversity, body distribution, cellular distribution, organelle distribution, and/or antioxidant properties and capabilities, etc. As such, prior art antioxidant compounds are useful for some applications, yet less or non-useful for other applications.
  • the present invention teaches novel compounds which are hydrolyzed in vivo to a plurality of different antioxidant species, which act in concert to reduce or prevent oxidative stress in a plurality of tissues, cell types and cellular organelles, so as to combat disease, syndromes and conditions associated with formation of oxidative stress both in the body periphery and in the brain.
  • an antioxidant compound which includes a peptide including at least three amino acid residues of which at least two are cysteine residues, each having a readily oxidizable sulfhydryl group which serves for effecting antioxidation.
  • the peptide which is an antioxidant in itself, also includes at least two peptide bonds each is cleavable by at least one intracellular peptidase.
  • the antioxidant compound of the present invention further includes a first hydrophobic or non-charged moiety which is attached to an amino terminal of the peptide via a first bond and a second hydrophobic or non-charged moiety which is attached to a carboxy terminal of the peptide via a second bond.
  • the first and second hydrophobic or non-charged moieties are selected so as to provide the antioxidant compound with membrane miscibility properties, for permitting the antioxidant compound to cross cellular membranes.
  • the antioxidant compounds of the present invention are characterized by the following unique and advantageous feature. Cleavage of the peptide bonds of the peptide by the intracellular peptidase(s) results in generation of a plurality of antioxidant species, each including at least one of the cysteine residues having the readily oxidizable sulfhydryl group and which is also active in effecting antioxidation, thereby providing a plurality of different antioxidant species acting in synergy in exerting antioxidation.
  • the antioxidant compound of the present invention is a peptide prodrug which penetrates the cells due to its solubility in the cell membrane.
  • the prodrug Upon entering the cytoplasm of a cell, the prodrug is cleaved by one or several intracellular peptidases, to release a plurality of different antioxidant species, each having at least one readily oxidizable sulfhydryl group to exert the antioxidative properties and acting in synergy in exerting antioxidation.
  • Each cleaved species acts according to its biological half-life and independently of the other generated species to exert antioxidation. It will be appreciated in this respect that different cells consist of a selective set of different peptidases/esterases.
  • prodrug refers to an agent which is converted into an active parent drug in vivo. Prodrugs are often useful because in some instances they may be easier to administer than the parent drug itself. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility compared to the parent drug in pharmaceutical compositions.
  • peptide includes native peptides (either degradation products, synthetically synthesized peptides or recombinant peptides) and peptidomimetics (typically, synthetically synthesized peptides), such as peptoids and semipeptoids which are peptide analogs, which may have, for example, modifications rendering the peptides more stable while in a body, or less immunogenic.
  • Such modifications include, but are not limited to, cyclization, N-terminus modification, C-terminus modification, peptide bond modification, including, but not limited to, CH 2 —NH, CH 2 —S, CH 2 —S ⁇ O, O ⁇ C—NH, CH 2 —O, CH 2 —CH 2 , S ⁇ C—NH, CH ⁇ CH or CF ⁇ CH, backbone modification and residue modification.
  • Methods for preparing peptidomimetic compounds are well known in the art and are specified, for example, in (53), which is incorporated by reference as if fully set forth herein. Further detail in this respect are provided hereinunder.
  • a peptide according to the present invention can be a cyclic peptide.
  • Cyclization can be obtained, for example, through amide bond formation, e.g., by incorporating Glu, Asp, Lys, Orn, di-amino butyric (Dab) acid, di-aminopropionic (Dap) acid at various positions in the chain (—CO—NH or —NH—CO bonds).
  • Cyclization via formation of S—S bonds through incorporation of two Cys residues, in addition to the Cys residues exerting antioxidation, is also possible. Additional side-chain to side chain cyclization can be obtained via formation of an interaction bond of the formula —(—CH 2 —) n —S—CH 2 —C—, wherein n 1 or 2, which is possible, for example, through incorporation of Cys or homoCys and reaction of its free SH group with, e.g., bromoacetylated Lys, Orn, Dab or Dap.
  • Peptide bonds (—CO—NH—) within the peptide may be substituted, for example, by N-methylated bonds (—N(CH 3 )—CO—), ester bonds (—C(R)H—C—O—O—C(R)—N—), ketomethylen bonds (—CO—CH 2 —), ⁇ -aza bonds (—NH—N(R)—CO—), wherein R is any alkyl, e.g., methyl, carba bonds (—CH 2 —NH—), hydroxyethylene bonds (—CH(OH)—CH 2 —), thioamide bonds (—CS—NH—), olefinic double bonds (—CH ⁇ CH—), retro amide bonds (—NH—CO—), peptide derivatives (—N(R)—CH 2 —CO—), wherein R is the “normal” side chain, naturally presented on the carbon atom.
  • Natural aromatic amino acids, Trp, Tyr and Phe may be substituted for synthetic non-natural acid such as TIC, naphthyl (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.
  • amino acid or “amino acids” is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodemosine, nor-valine, nor-leucine and ornithine.
  • amino acid includes both D- and L-amino acids which are linked via a peptide bond or a peptide bond analog to at least one addition amino acid as this term is defined herein.
  • amino acid residue is understood to be an amino acid as this term is defined herein when serving as a building block or unit in a peptide, as this term is defined herein.
  • Non-conventional or modified amino acids Non-conventional amino acid Code
  • Non-conventional amino acid Code Non-conventional amino acid Code ⁇ -aminobutyric acid Abu L-N-methylalanine Nmala ⁇ -amino- ⁇ -methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn carboxylateXXX XX L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgin CarboxylateXXX XX L-N-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine Nmile D-alanine Dal L-N-methylleucine
  • the antioxidant compound has the general formula: A-Y1-Cys-Y2-Cys-Y3-B wherein, Cys is a cysteine residue, A is the first hydrophobic or non-charged moiety; B is the second hydrophobic or non-charged moiety; Y1, Y2 and Y3 are each individually one or more amino acid residues in the range of 0-30, preferably 0-20, more preferably 0-10, most preferably 0-5, 0-4, 0-3, 0-2 or 0-1 amino acid residues, with the provision that Y1, Y2 and Y3 collectively provide for at least two amino acid residues in the peptide.
  • a compound which has the above listed properties and which is hydrolyzable within a cell so as to generate a plurality of antioxidant species acting in concert is for example: A-Cys-A1-A2-Cys-B (SEQ ID NO: 2)
  • A1 and A2 are amino acid residues.
  • This tetra-peptide having hydrophobic or non-charged moieties (A and B) at the N and C terminals and which is an antioxidant by itself, is hydrolyzable in vivo to yield additional 14 antioxidant species, each having at least one cysteine residue, each of which is active in effecting antioxidation by virtue of the functional CH 2 —SH-group of the cysteine residue thereof: 1.
  • A-Cys SEQ ID NO: 3
  • A-Cys-A1 SEQ ID NO: 4
  • A-Cys-A1-A2 SEQ ID NO: 5
  • A-Cys-A1-A2-Cys SEQ ID NO: 6
  • Cys-A1-A2-Cys-B (SEQ ID NO: 7) 6. A1-A2-Cys-B (SEQ ID NO: 8) 7. A2-Cys-B (SEQ ID NO: 9) 8. Cys-B (SEQ ID NO: 10) 9. Cys-A1-A2-Cys (SEQ ID NO: 11) 10. Cys-A1-A2 (SEQ ID NO: 12) 11. Cys-A1 (SEQ ID NO: 13) 12. Cys (SEQ ID NO: 14) 13. A1-A2-Cys (SEQ ID NO: 15) 14. A2-Cys (SEQ ID NO: 16)
  • a specific example of an A-Cys-A1-A2-Cys-B (SEQ ID NO:2) tetrapeptide antioxidant compound is N-Acetyl Cysteine-Glycine-Proline-Cysteine-Amid (SEQ ID NO:1), which compound is designated in the Examples section that follows as CB and has the following chemical structure: CH 3 CO—NH—CH(CH 2 SH)CO—NHCH 2 CO—N(CH 2 —CH 2 —CH 2 )—CO—NH—CH(CH 2 SH)—CO—NH 2
  • Another compound which has the above listed properties and which is hydrolyzable within a cell so as to generate a plurality of antioxidant species acting in concert is for example the tripeptide having the general formula: A-Cys-A1-Cys-B (SEQ ID NO: 17)
  • This tripeptide can be hydrolyzed in vivo to yield an additional 9 species, each having at least one cysteine residue which is active in effecting antioxidation by virtue of the functional CH 2 —SH-group thereof: 1.
  • A-Cys (SEQ ID NO: 3) 2.
  • A-Cys-A1 (SEQ ID NO: 4) 3.
  • A-Cys-A1-Cys (SEQ ID NO: 18) 4.
  • Cys-A1-Cys-B SEQ ID NO: 19) 5.
  • Cys-A1-Cys SEQ ID NO: 20
  • A1-Cys SEQ ID NO: 21
  • Cys-A1 SEQ ID NO: 13
  • Cys-B (SEQ ID NO: 10) 9. Cys (SEQ ID NO: 14)
  • living cells include a repertoire of peptidases capable of hydrolyzing a peptide bond formed between any pair of amino acid residues in a peptide.
  • Some peptidases are more specific than others, they may have different abundancy and subcellular distribution, so as to result in some antioxidant species being more represented than others in a certain cellular environment.
  • the antioxidant To successfully protect biological systems from oxidants, the antioxidant must have a higher reactivity for the oxidant than the biologic molecule which it seeks to protect. To protect the desired biologic system from oxidation, it is also necessary for the antioxidant to partition itself adjacent to the molecule to be protected. As an example, a molecule to be protected within the lipid bilayer of plasma, endosomal or nuclear membranes might be best protected by an antioxidant with, at least in part, a lipophilic structure, so that it is partitioned to or near the lipid portion of the membrane, adjacent to the molecule needing protection from oxidation.
  • the hydrophobic or non-charged moieties conjugated to the antioxidant peptides of the present invention can be of any type which will render the compound sufficiently hydrophobic or non-charged so as to penetrate into the cytoplasm via its membrane miscibility properties.
  • the exact type will of course depend on the peptide itself, as some peptides are more hydrophobic or non-charged than others.
  • the compound of the present invention should be designed sufficiently hydrophobic or non-charged so as to cross blood barriers, such as, BBB, blood retinal barrier and blood testis barrier.
  • living cells are also characterized by a large repertoire of other hydrolases such as, but not limited to, esterases and amidases, which are effective in hydrolyzing the bonds between the hydrophobic or non-charged moieties A and/or B and the peptide in-between, so as to increase the repertoire of antioxidant species released inside the cell.
  • This cleavage action has an additional effect. Removal of one or both of the hydrophobic or non-charged moieties results in decrease in the total hydrophobic or non-charged moiety of the antioxidant species thus generated and as a result, the formed species are advantageously trapped in the cells, so as to efficiently exert their antioxidant properties therein.
  • cleavage of the first bond and/or the second bond which connect between the hydrophobic or non-charged moieties A and/or B by a cellular hydrolase results in loss of membrane miscibility, therefore the antioxidant species are trapped within the cell so as to exert their antioxidant activity.
  • Each of the first and second hydrophobic or non-charged moieties can independently be, for example, alkyl, aryl, alkene, arene or cholesteril having a backbone of 1-50 carbon atoms.
  • alkyl refers to a saturated aliphatic hydrocarbon group having a linear or branched backbone.
  • the alkyl has 1 to 20 carbon atoms in its backbone.
  • a numerical range e.g., “1-20”, is stated herein, it means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms.
  • the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioa, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, sulfonamido, trihalomethanesulfonamido, silyl, guanyl, guanidino, ureido, amino or NR 10 R 11 , wherein R 10 and R 11 , are each independently hydrogen, alkyl, cycloalkyl, aryl, carbonyl, sulfonyl, trihalometh
  • a “cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein, one of more of the rings does not have a completely conjugated pi-electron system.
  • examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane.
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, nitro, amino and NR 10 R 11 as defined above.
  • alkenyl refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon triple bond.
  • aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and NR 10 R 11 as defined above.
  • heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino or NR 10 OR 11 as defined above.
  • a “heteroalicyclic” group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be substituted or unsubstituted.
  • the substituted group can be, for example, alkyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, sulfinyl, sulfonyl, C-amido, N-amido, amino and NR 10 R 11 as defined above.
  • each of the hydrophobic or non-charged moieties identified herein by A and B is independently N-acetyl, tert butyl, isopropyl, n-butyl, n-pentyl, amide or ester.
  • a compound according to the present invention can be administered per se to an organism, such as a human being or any other mammal, or in a pharmaceutical composition where it is mixed with suitable carriers or excipients.
  • compositions for preventing or reducing oxidative stress comprising a pharmaceutically acceptable carrier and, as an active ingredient, an antioxidant compound as described hereinabove.
  • a “pharmaceutical composition” refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or prodrugs thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • compositions may also include one or more additional active ingredients, such as, but not limited to, anti-inflammatory agents, antimicrobial agents, anesthetics in addition to the antioxidant compounds.
  • additional active ingredients such as, but not limited to, anti-inflammatory agents, antimicrobial agents, anesthetics in addition to the antioxidant compounds.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions herein described may also comprise suitable solid of gel phase carriers or excipients.
  • suitable solid of gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of antioxidant preparation effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the IC 50 and the LD 50 (lethal dose causing death in 50% of the tested animals) for a subject compound.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See e.g., (54).
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • the present invention can be used to treat any one of a plurality of diseases, disorders or conditions associated with the formation of oxidative stress.
  • the term “treat” include substantially inhibiting, slowing or reversing the progression of a disease, disorder or condition, substantially ameliorating clinical symptoms of a disease disorder or condition, or substantially preventing the appearance of clinical symptoms of a disease, disorder or condition.
  • the compounds of the present invention can be used to treat non-central nervous system disorders such as rheumatoid arthritis, cataract, Down syndrome, cystic fibrosis, diabetes, acute respiratory distress syndrome, asthma, post-surgical neurological dysfunction, amyotrophic lateral sclerosis, atherosclerotic cardiovascular disease, hypertension, post-operative restenosis, pathogenic vascular smooth muscle cell proliferation, pathogenic intra-vascular macrophage adhesion, pathogenic platelet activation, pathogenic lipid peroxidation, myocarditis, stroke, multiple organ dysfunction, complication resulting from inflammatory processes, AIDS, cancer, aging, bacterial infection, sepsis; viral disease, such as AIDS, hepatitis C, an influenza and a neurological viral disease, all of which were previously shown to be associated with the formation and/or overproduction of oxidants and habits resulting in oxidative stress, such as, but not limited to, smoking, sun tanning, cancer treatment, radiation cocaine consumption and morphine consumption.
  • non-central nervous system disorders such as r
  • the compounds of the present invention can also be used to treat a central nervous system disorder characterized by oxidative stress, such as, neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, cerebral ischemia, multiple sclerosis, degenerative diseases of the basal ganglia, motoneuron diseases, scrapies, spongiform encephalopathy, neurological viral diseases, motoneuron diseases, post-surgical neurological dysfunction and loss or memory impairment, all of which were previously shown to be associated with the formation and/or overproduction of oxidants and habits resulting in oxidative stress, such as, but not limited to, smoking, sun tanning, cancer treatment, radiation cocaine consumption and morphine consumption.
  • oxidative stress such as, neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, cerebral ischemia, multiple sclerosis, degenerative diseases of the basal ganglia, motoneuron diseases, scrapies, spongiform encephalopathy, neurological viral diseases,
  • CB N-Acetyl Cysteine-Glycine-Proline-Cysteine-Amid
  • CB was prepared by solid phase synthesis of peptides according to published protocols. The synthesis was carried out according to Fastmoc 0.25 mmol modules in a peptide synthesizer Model 433A (Applied Biosystems) according to the User's manual.
  • 9-fluorenylmethoxycarbonyl (Fmoc) amino acid (1 mmol) was dissolved and activated in the cartridge in a mixture of 3.0 g of 0.45 M 2-(1H-benzoltriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU/HOBt) in DMF, 2 M Diisopropyethylamine (DIEA) and 0.8 ml N-methyl-pyrrolidone (NMP). De-protection was carried out in 22% piperidine solution in NMP. All steps were carried out under nitrogen.
  • HBTU/HOBt 2-(1H-benzoltriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DIEA Diisopropyethylamine
  • NMP N-methyl-pyrrolidone
  • the resin was de-protected as follows: Fmoc-Benzhydrylamine resin (368 mg; 0.25 mmol) was stirred in N-methyl pyrrolidone (7 ml). De-protection was carried out by washing the resin with 22% piperidine/NMP solution for 2 minutes. The solvents were removed and the resin was subjected to a second treatment with 22% piperidine/NMP for 7.6 minutes. Then, the resin was washed 6 times with DCM, followed by 4 washes in NMP.
  • Step 1 Fmoc-trityl cysteine (0.454 g) was reacted for 6 min in NMP (2 g) together with 0.9 mmol of 0.45M HPTU/HOBt in DMF (2 g). De-protection was carried out as outlined above.
  • Step 2 Fmoc-proline (0.478 g) was reacted for 6 min in NMP (2 g) together with 0.9 mmol of 0.45 M BPTU/HOBt in DMF (2 g). De-protection was carried out as outlined above.
  • Step 3 Fmoc-glycine (0.493 mg) was reacted for 6 min in NMP (2 g) together with 0.9 mmol of 0.45 HPTU/HOBt in DMF (2 g). De-protection was carried out as outlined above.
  • Step 4 Fmoc-trityl cysteine (0.454 g) was reacted for 6 min in NMP (2 g) together with 0.9 mmol of 0.4 5M HPTU/HOBt in DMF (2 g). De-protection was carried out as outlined above.
  • Step 5 Acetic anhydride (0.534 g) was reacted 6 min in NMP (2 g) together with 0.9 mmol of 0.45M HPTU/HOBt in DMF (2 g).
  • Step 6 The resin was mixed using a vortex with 95% TFA/2.5% DDW/2.5% triisopropyl silane for 10 min at 40° C. and 2 hours at room temperature. The mixed resin was filtered and the resulting peptide was precipitated with cold ether. The precipitate was washed 4 times with cold ether, next 10% acetic acid was added followed by lyophilization.
  • the yield of the above synthesis was 80 mg of the CB molecule.
  • NIH3T3 cells overexpressing EGF receptor (DHER14 cells) (55) were exposed to cisplatin (CDDP, 30 ⁇ M) which activates specific enzymes involved in apoptosis including JNK and p38.
  • ROS reactive oxygen species

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