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

a technology of antioxidant compounds and pharmaceutical compositions, which is applied in the direction of dipeptides, peptide/protein ingredients, depsipeptides, etc., can solve the problems of unacceptably risky administration routes, cumbersome and invasive, ineffective reduction,

Inactive Publication Date: 2011-08-04
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such a route of administration, however, is unacceptably risky, cumbersome and invasive and thus represents a major drawback for this treatment modality.
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.
As such, any given antioxidant may prove useful for some applications, yet less or non-useful for other applications.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of N-Acetyl Cysteine-Glycine-Proline-Cysteine-Amid

[0135]The synthesis of N-Acetyl Cysteine-Glycine-Proline-Cysteine-Amid (CB, SEQ ID NO:1) having the chemical structure of:

CH3CO—NH—CH(CH2SH)CO—NHCH2CO—N(CH2—CH2—CH2)CH—CO—NH—CH(CH2SH)—CO—NH2

(molecular weight of 406) is described herein.

[0136]Synthesis: 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.

[0137]In particular, 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.

[0138]De protect...

example 2

Inhibition of JNK (c-Jun NH2-terminal kinase) and p38 enzymes

[0146]In order to show the efficacy of CB against a stimulant that activates oxidative stress, an inhibition assay of both JNK (c-Jun NH2-terminal kinase) and p38 enzymes in tissue culture was performed.

[0147]NIH3T3 cells overexpressing EGF receptor (DHER14 cells) (55) were exposed to cisplatin (CDDP, 30 μM) which activates specific enzymes involved in apoptosis including JNK and p38.

[0148]As shown in FIG. 2, JNK or p38 were detected by specific antibodies essentially as previously described (6). In the presence of increasing concentrations of CB, a dramatic reduction in the phosphrylated form of either p38 or JNK enzymes was obtained. In the presence of 20 μM CB, phosphorylated p38 and JNK enzymes were not detected at all. Two known antioxidants were used as positive controls, NOXi (at 300 and 1000 μM) and NAC (NAC) (at 1000 μM). The efficacy of CB at 20 μM was similar to that obtained by the addition of 1 mM of N-acetyl ...

example 3

Inhibition of ROS Production

[0149]The concentration of reactive oxygen species (ROS) in DHER14 cells following administration of antioxidants was determined using the ROS sensitive fluorescent dye DHDCF (fluoresceine derivative). As shown in FIG. 3, reduction of ROS below normal levels was prominent in the presence of 20 μM of CB. Two known antioxidants were used as control, NOXi (at 1000 μM) and NAC (NAC) (at 1000 μM). The efficacy of CB in reducing ROS was about ˜50 fold better then these two known antioxidants. Thus, at 20 μM CB was as efficient as 1000 μM NAC or 1000 μM NOXi.

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Abstract

An antioxidant compound is disclosed. The compound is characterized by (a) a peptide including at least three amino acid residues of which at least two are 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 one of the cysteine residues having the readily oxidizable sulfhydryl group and which is also active in effecting antioxidation, thereby providing for a plurality of different antioxidant species acting in synergy in exerting antioxidation.

Description

RELATED APPLICATION / S[0001]This application is a continuation of pending U.S. patent application Ser. No. 11 / 797,590 filed on May 4, 2007, which is a continuation of U.S. patent application Ser. No. 10 / 234,319 filed on Sep. 5, 2002, now abandoned, which is a National Phase of PCT Patent Application No. PCT / IL01 / 00984 having International Filing Date of Oct. 25, 2001, which claims the benefit of priority of United Kingdom Patent Application No. 0026254.3 filed on Oct. 26, 2000, now Patent No. GB2368339. The contents of the above applications are all incorporated herein by reference.FIELD AND BACKGROUND OF THE INVENTION[0002]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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/07C07K5/103A61P3/10A61P31/04A61P31/18A61P31/14A61P9/12A61P9/10A61P35/00A61P25/28A61P25/00A61P7/00A61P11/06A61P39/06A61K38/00A61K9/18A61K9/40A61P7/02A61P9/00A61P11/00A61P17/16A61P19/02A61P25/16A61P25/30A61P25/34A61P25/36A61P27/12A61P29/00A61P31/12A61P31/16A61P39/00A61P41/00A61P43/00C07K5/06C07K5/08C07K5/083C07K5/10C07K7/06C07K7/08C07K14/00
CPCA61K38/00C07K5/1013C07K5/081C07K5/0606A61P11/00A61P11/06A61P17/16A61P19/02A61P25/00A61P25/16A61P25/28A61P25/30A61P25/34A61P25/36A61P27/12A61P29/00A61P31/04A61P31/12A61P31/14A61P31/16A61P31/18A61P35/00A61P39/00A61P39/06A61P41/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10A61P9/12A61P3/10
Inventor ATLAS, DAPHNE
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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