MXPA96004499A - Chlorate forming agent of novedous iron, as inhibitor of hid mediated oxidation - Google Patents
Chlorate forming agent of novedous iron, as inhibitor of hid mediated oxidationInfo
- Publication number
- MXPA96004499A MXPA96004499A MXPA/A/1996/004499A MX9604499A MXPA96004499A MX PA96004499 A MXPA96004499 A MX PA96004499A MX 9604499 A MX9604499 A MX 9604499A MX PA96004499 A MXPA96004499 A MX PA96004499A
- Authority
- MX
- Mexico
- Prior art keywords
- iron
- group
- composition
- deferriexoquelines
- mammal
- Prior art date
Links
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims description 108
- 229910052742 iron Inorganic materials 0.000 title claims description 55
- 230000001404 mediated Effects 0.000 title claims description 5
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 2
- 230000003647 oxidation Effects 0.000 title description 2
- 238000007254 oxidation reaction Methods 0.000 title description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 title 2
- 239000003795 chemical substances by application Substances 0.000 title 1
- 210000001519 tissues Anatomy 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000012530 fluid Substances 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 210000000056 organs Anatomy 0.000 claims abstract description 7
- 230000017531 blood circulation Effects 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000005755 formation reaction Methods 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 206010022114 Injury Diseases 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl radical Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 6
- 230000003405 preventing Effects 0.000 claims description 6
- 210000004165 Myocardium Anatomy 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical group NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229960001663 sulfanilamide Drugs 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 230000003902 lesions Effects 0.000 abstract description 2
- 150000002632 lipids Chemical class 0.000 abstract description 2
- 210000004027 cells Anatomy 0.000 description 32
- 229910052751 metal Inorganic materials 0.000 description 18
- 239000002184 metal Substances 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 201000008827 tuberculosis Diseases 0.000 description 11
- 150000002739 metals Chemical class 0.000 description 9
- 206010063837 Reperfusion injury Diseases 0.000 description 7
- 102000004338 Transferrin Human genes 0.000 description 7
- 108090000901 Transferrin Proteins 0.000 description 7
- NGQYHMUFXKSYFU-BWAHOGKJSA-N [3-[(1-hydroxy-2-oxoazepan-3-yl)amino]-3-oxopropyl] 7-[formyl(hydroxy)amino]-2-[[(2Z)-2-(6-oxocyclohexa-2,4-dien-1-ylidene)-1,3-oxazolidine-4-carbonyl]amino]heptanoate Chemical compound C1CCCN(O)C(=O)C1NC(=O)CCOC(=O)C(CCCCCN(O)C=O)NC(=O)C(N1)CO\C1=C1\C=CC=CC1=O NGQYHMUFXKSYFU-BWAHOGKJSA-N 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000012581 transferrin Substances 0.000 description 7
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000797 iron chelating agent Substances 0.000 description 5
- 230000000302 ischemic Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 102000008857 Ferritin Human genes 0.000 description 4
- 108050000784 Ferritin Proteins 0.000 description 4
- 238000008416 Ferritin Methods 0.000 description 4
- 102000003855 L-lactate dehydrogenases Human genes 0.000 description 4
- 108091000084 L-lactate dehydrogenases Proteins 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- 210000004413 Myocytes, Cardiac Anatomy 0.000 description 4
- WLJVNTCWHIRURA-UHFFFAOYSA-N Pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
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- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 241000894007 species Species 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QJHBJHUKURJDLG-YFKPBYRVSA-N (2S)-6-amino-2-(hydroxyamino)hexanoic acid Chemical compound NCCCC[C@H](NO)C(O)=O QJHBJHUKURJDLG-YFKPBYRVSA-N 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 229940075525 Iron chelating agents Drugs 0.000 description 3
- 102000010445 Lactoferrin Human genes 0.000 description 3
- 108010063045 Lactoferrin Proteins 0.000 description 3
- 229940078795 Lactoferrin Drugs 0.000 description 3
- 208000010125 Myocardial Infarction Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
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- 229940079593 drugs Drugs 0.000 description 3
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- 235000021242 lactoferrin Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 media Substances 0.000 description 3
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- 239000000243 solution Substances 0.000 description 3
- 102000020504 Collagenase family Human genes 0.000 description 2
- 108060005980 Collagenase family Proteins 0.000 description 2
- 229960000958 Deferoxamine Drugs 0.000 description 2
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- 108010035210 Iron-Binding Proteins Proteins 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 241001467553 Mycobacterium africanum Species 0.000 description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 230000002458 infectious Effects 0.000 description 2
- 150000002505 iron Chemical class 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 210000000663 muscle cells Anatomy 0.000 description 2
- 210000000107 myocyte Anatomy 0.000 description 2
- 230000004792 oxidative damage Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
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- 239000012588 trypsin Substances 0.000 description 2
- 238000002562 urinalysis Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N β-Alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 206010000891 Acute myocardial infarction Diseases 0.000 description 1
- FRHBOQMZUOWXQL-UHFFFAOYSA-L Ammonium ferric citrate Chemical compound [NH4+].[Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FRHBOQMZUOWXQL-UHFFFAOYSA-L 0.000 description 1
- 102000006734 Beta-Globulins Human genes 0.000 description 1
- 108010087504 Beta-Globulins Proteins 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
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- 210000002421 Cell Wall Anatomy 0.000 description 1
- 210000004351 Coronary Vessels Anatomy 0.000 description 1
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- 102000001974 Hyaluronidase Human genes 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
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- 241000187473 Mycobacterium aurum Species 0.000 description 1
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- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 241000187478 Mycobacterium chelonae Species 0.000 description 1
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- 241000187913 Mycobacterium chubuense Species 0.000 description 1
- 241001532524 Mycobacterium duvalii Species 0.000 description 1
- 241000187911 Mycobacterium farcinogenes Species 0.000 description 1
- 241000187486 Mycobacterium flavescens Species 0.000 description 1
- 241000186365 Mycobacterium fortuitum Species 0.000 description 1
- 241000187470 Mycobacterium gadium Species 0.000 description 1
- 241000187485 Mycobacterium gastri Species 0.000 description 1
- 241000187484 Mycobacterium gordonae Species 0.000 description 1
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- 241000187493 Mycobacterium malmoense Species 0.000 description 1
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- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to a composition for protecting living tissue in a mammal, from a lesion resulting from exposure to the hydroxyl-free radical formed after re-establishment of fluid flow to an organ of the body after restriction of blood flow to This organ of the body, characterized in that it comprises an effective amount of a water-soluble lipid and deferriexoqueline, the amount being effective to protect the mammal in restoring fluid flow to the tissue.
Description
FORMER FORMER OF IRON QUALATES, NOVEDOUS, AS INHIBITOR OF IRON MEDIATED OXIDATION
This invention was made in part with the governmental support of NIH Grant AI-33790 and NIH Grant HL-8177.
The present invention relates to the chemical structure of a previously unidentified series of high-affinity iron binding compounds, referred to by previous investigators as exo-leaflets, which are released by mycobacteria. The invention also relates to modifications for these newly identified compounds, to vary their physiological properties and applications of these newly identified and modified compounds. In acute myocardial infarction, cardiac tissue is damaged by two sequential events, hypoxia in the ischemic phase and oxidative damage in the reperfusion phase. The damaged myocardium in the ischemic phase can be rehabilitated by reintroducing blood to the ischemic area. However, reperfusion may result in injury as a result of an inflammatory response in the reperfused tissue caused by the migration of leukocytes within the tissue REF: 23177 and the production of reactive oxygen species. One of the most reactive species is the hydroxyl species (• OH) which is generated in the presence of iron and which results in the death of the cell. The prevention of the formation of (»0H) will prevent the lethal damage of the cell from this cause. It is known that the formation of (* 0H) is dependent on the presence of free iron and that the iron chelating agents will prevent reperfusion injury. For example, desferoxamine of iron chelating agents, when administered before reperfusion, prevents injury and reduces the size of myocardial infarction during occlusion and reperfusion of the coronary artery. However, reperfusion injury occurs rapidly after the reestablishment of blood flow to the ischemic myocardium. Radical formation (# 0H) is dependent on the presence of free iron; Iron chelating agents can remove free iron and thus convert unusable iron to catalyze the formation of hydroxyl radicals. However, any of these materials for the formation of iron chelates known above do not impede the production of (ß0H) by the Fenton reaction (ie, EDTA), or introduce the slow-deficient cells (ie, desferoxamine) in a manner such that sufficient quantities are not available to act fast enough to form sufficient iron chelates to prevent the formation of (»0H) and subsequent cell destruction. Desferrioxamine has been shown to be effective if it is administered before it occurs. myocardial infarction but it is ineffective if administered at or after the start of reperfusion. A similar injury to heart tissue may occur as a result of bypass procedures of the heart, such as during surgery of the heart exposed to air, or other organs of the body when these are deprived of oxygenated blood as a result of surgery or injury. Exoquelines were briefly described and their general function in the growth of mycobacteria was discussed by Macham, Ratledge and Barclay at the University of Hull in England (Lionel P. Macham, Colin Ratledge and Jennifer C. Nocton, "Extracellular Iron Acquisition by Mycobacteria: Role of the Exochelins in Evidence Against the Participation of Mycobactin, "Infection and Immunity, Vol. 12, No. 6, p.122.2-1251, Des. 1975; Raymond Barclay and Colin Ratlege," Mycobacterium and Exochelins of Mycobacterium tuberculosis, M Bovis, M. africanum and Other Related Species, "Journal of General Microbiology, 134, 771-776, (1988); LP Macham and C. Ratledge," A New Group of Water-soluble Iron-binding
Compounds from Mycobacteria: The Exochelins ", Journal of General Microbiology, 89 379-282, (1975)). Macham identified the existence of a substance found in the extracellular fluid, which he referred to as exoquelin. He described exoquelin as a soluble compound in water and soluble chloroform that has the ability to chelate free iron. According to Macham, this material has similarities to mycobactin, which is located in the cell wall and works to transmit iron to the interior of the cell. However, in contrast to this, mycobactin is a molecule insoluble in lipophilic water that is unable to expand inside, and assimilate free iron from the extracellular environment. Macham et al. Recognized that the functions of exochole at a physiological pH separates iron from other iron-bearing compounds in serum, such as transferrin (amber crystalline protein) or ferritin (beta-globulin in the blood plate), and the iron present in a form that can be transferred to mycobactin. Macham et al. Did not isolate or purify the exochleoli but identified them as a penta- or hexapeptides, having a molecular weight of 750 to 800, containing 3 moles of (N-hydroxylysine, N-acetyl-cN-hydroxylysine or? N-hydroxiornitine and 1 mole of threonine (crystalline alpha-amino acid) Also depending on the exoCein's Dacterial source, he discovered that the molecules "can also include beta-alanine or salicylic acid." Barclay (ibid) described the production of exocoils to From twenty-two different classes of M. tuberculosis and related species, however, these previous investigators did not determine the specific structure of the exocoils or identified any application of the exocoils different from their function as a transport medium for iron to localized microbactin In this way there is a need for a substance that can be easily administered at the time of rep erfusion and which rapidly chelates free iron as this form or makes available to prevent radical formation ("OH"). In addition, there is a need to identify the specific structure of the exoquelin so that its function can be more fully understood and its utility as a diagnostic, treatment and preventive modality can be clarified.
BRIEF DESCRIPTION OF THE INVENTION
These needs are met by the present invention which comprises the use of exo-lines to prevent damage to tissues of living beings from the formation or presence of the radical (»0H). In particular, the invention is directed to the administration of extrudes to the infarcted myocardium before or coinciding with reperfusion to prevent damage to the myocardium from the formation of free radicals mediated by iron. The chemical structure of modified extrudes and extrudes as well as other applications of other materials in the treatment and diagnosis of diseases in mammals is also represented.
DRAWINGS
These and other features, aspects and advantages of the present invention will become better understood with respect to the following description, appended claims and accompanying drawings, wherein:
Figure 1 shows the chemical structure of an iron chelate of an exoquelin molecule (ferriexoquelin) and desferriexoquelin (iron free).
Figure 2 shows an elution profile of a filtered culture liquid of M. tuberculosis, monitored at 220 nm and 450 nm.
Figure 3 shows an elution profile of the same filtered liquid monitored at 4-50 nm with the molecular weight of each peak shown.
Figure 4- shows the spectra of the mass spectrometer of an exocole containing main serine at m / z = 720.3 together with the determined structure thereof.
Figure 5 is a graph showing the inhibition of cell injury as a result of the use of an exocole mixture in cardiac myocytes.
Figure 6 is a graph showing the inhibition of cell injury as a result of the use of exoquelin 758C in cardiac myocytes.
Figure 7, 8 and 9 are graphs comparing the inhibition of cell injury as a result of the use of exoquelin 758C, 772A and 772C in cardiac myocytes.
Figure 10 shows the chemical structure of an iron chelate of exoquelin (ferriexoquelin) and the molecule of desferriexoquelin (free of iron) with cytos for identified modification.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that exocoils can block, or significantly reduce, oxidative damage to tissues as a result of tissue-mediated iron catalysis / free radical reactions, such as the hydroxyl radical (* 0H), particularly hydroxyl radicals generated in the Fenton reaction, commonly referred to as reperfusion injury. It has also been found that exochelines are effective in delaying or preventing reperfusion injury when administered at the onset of, or concurrent with, reperfusion. Additionally, it has been found that exo-lines include a much broader class of materials and that they have a different chemical structure then originally speculated by Macham et al. And Barclay et al. It has also been found that these materials can form chelates from a wide range of metals to result in previously unknown materials. In addition to preventing reperfusion injury, appropriately modified exoplanes can be used to treat certain diseases, attack certain cells, such as cancer cells, and be used to monitor the effectiveness of drug treatment and detect the presence of certain conditions. the illness. In particular, it is known that the growth of neuroblastoma cells can be adversely affected by iron removal using desferrioxamine iron chelate-forming compound without similarly affecting the growth of normal cells. Other applications of exocoils include the treatment of iron overload of transfusions or cancer chemotherapy, particularly for leukemia. As a result of the isolation and purification of exo-lines, it has been found that exo-lines are a family of molecules that have a range of molecular weights and various different side chains. further, purified extructors have been prepared and their usefulness as free iron scavengers, such that they are effective in preventing the formation of hydroxyl radicals (* 0H) that damage tissue, has been demonstrated for the first time. In particular, the purified exoquelines of M. tuberculosis have been isolated and have been shown to effectively remove iron from transferrin, lactoferrin and ferritin at a physiological pH without transmitting any of the infectious properties of the bacteria from which they are derived. It has also been shown for the first time that these exocoils block the formation of hydroxyl radicals by the Fenton reaction and, based on the response of cardiac myocytes, they can be effective to prevent reperfusion injury after myocardial infarction or vascular trauma or attack to another tissue when they are administered after the "taque" occurs as well as for several hours after the incident. While mycobactins have been studied extensively, individual exocoils have not been isolated or purified and their structure and composition has not been previously defined. Furthermore, it has been found that the above references have erroneously characterized the ex-quelines, and thus have failed to identify the structure of these compounds. In particular, Macham (ibid) identified them as a penta- or hexapeptide, having a molecular weight of 750 to 800, which contains 3 moles of N-hydroxylysine, fN-acetyl-N-hydroxylysine, or N-hydroxyioritine and mol of threonine. It has been found that exo-lines have a much broader range of molecular weights, which constitute several series of compounds with an identifiable difference in molecular weights, include only 2 moles of € -N-hydroxylysine and are not peptides. A peptide is a polymer of an amino acid (NH-CHR-COOH) formed by the condensation of the carboxylic group of a first molecule with the amino group of another molecule to form an amide bond (-C0-NH-). Exoquelines can not be considered to be peptides. Instead, they contain three amino acids and other structural portions (salicylic acid, dicarboxylic acids or mono ester analogs, and hydroxycarboxylic acids) formed by amide (-NH-C0-), hydroximate (-NH (OH) -CO-) and ester condensations (-CO-O -) The ferri and deferri forms are shown in Figure 1.
Preparation - Exuchelines were generated and purified from a virulent (Erdman) and non-virulent (H37Ra) strain of M. tuberculosis. To increase the production of M. tuberculosis exocoils, the bacteria were cultured in an iron-deficient medium. In particular, the Erdman strain of M. tuberculosis (American type culture collection 35801) and H37Ra (ATCC 25177) were grown on Middlebroo 7H11 agar plates at 37 ° C in 5% C02. After U days, the bacteria were harvested, suspended in 150 ml of the modified Sauton medium in culture flasks and incubated for 3 to 8 weeks. The modified Sauton medium contained 0.12 mg / l of ferric ammonium citrate without the addition of surfactant. Iron-enriched exo-lines (ferriexoquelines) were then recovered by filtration, iron-saturated and chloroform extraction and purified by high-pressure liquid chromatography (HPLC). Specifically, the fluid from the supernatant of the above suspension was filtered through consecutive 0.8 μm and 0.2 μm protein low-binding filters. The exocoils were then loaded with iron by saturating the filtered supernatant fluid by exposure to ferric chloride (150 mg per liter of culture filtrate). The ferriexoquelines were mixed with chloroform (1 volume of culture filtered liquid per 1.5 volumes of chloroform) and, after separation of the layers, the chloroform layer enriched with exocole was then removed and stored under anhydrous magnesium sulfate (2). g / l). The chloroform extract was then passed through a porous glass filter and evaporated by rotary evaporation leaving behind a brown residue. The brown residue was further purified by suspending in 5 ml of a first buffered solution (0.1% trifluoroacetic acid) which was introduced into a liquid chromatography column (C-18 Sep-Pak cartridge). The brown band that formed near the top of the column was eluted with a second buffer (1% TFA, 50 Z acetonitrile). The partially purified material was then diluted in three parts in 0.1% trifluoroacetic acid and subjected to reverse phase high pressure liquid chromatography at a rate of 1 ml / min followed by exposure to a C-18 column. The presence of iron-enriched exo-lines in the HPLC eluate is detected by simultaneous monitoring of the UV absorbance of the 4-50 nm peak (iron compounds) and the 220 nm peak which is indicative of the groups. amide and aromatic Approximately the peaks - u -5 major and 10 minor, shown in Figure 2, eluted outside the final C18 column exhibited a high absorbance ratio at 450/220 nm. These were confirmed to be extruded by mass spectrometry. The major peaks were further purified by a second reverse phase HPLC on an alkylphenyl column. The exoquelines recovered from the Erdman strain of M. tuberculosis were identical to the exoquelines recovered from the H37Ra strain.
Characterization - Based on the LSIMS and ESI-MS analysis of the numerous peaks, in their ferri- (fe 3+) form eluted from the column (see Figure 3), iron exo-lines are not limited to the two specific molecules detailed above but include a family of species that vary in masses from 716 to 828 daltons. Each member of the family looks different from its neighbor by 14-daltons, reflecting the number of CH groups in the alkyl side chain in Rj and / or 2 daltons, reflecting the presence of a double bond in the alkyl side chain in R *. Therefore, the exo-lines appear to form two series with the subsequent members of each series differing in masses by 14-daltons, the saturated series have masses of approximately 716, 730, 744, 758, 772, 786, 800, 81 and 828 daltons and the unsaturated series have masses of 742, 756, 770, 784., 798, 812 and 826. Additionally, the presence or absence of a methyl group in R (ie, H or CH) further defines two series of additional referenced molecules such as serine (R- = H) and the threonine series ( R = CH.,), As confirmed by the amino acid analysis. The most polar compounds are to the left of the figure (anterior eluate) and the less polar ones (more soluble in lipid) are to the right. However, all peaks are soluble in water. Where it was found that more than one peak has the same molecular weight, each peak was additionally designated A, B or C (ie 758A, B and C) to indicate the level of polarity with A representing the most polar compound and C representing the least polar form. The most polar forms are believed to result from methyl groups attached to different locations in the molecule.
Structure of the Exoquelin - Figure 4- shows the results of double mass spectrometric analysis under induced dissociation (He floated at 2 keV for a collision energy of 6 keV) of the highest serine-containing deferrioxoel, saturated with (M + H ) am / z 720.3. The fragment ions were assigned to one of the six structural portions AF resulting from the cleavage products generated around the amide or ester linkages with the hydrogen transfer relative to the neutral molecule associated with each peak indicated in the spectrum shown in Figure 4 - Hydrolysis and acid methylation of the exo-lines resulted in the formation of salicylic acid and pimelic acid. The mass spectrographic analysis indicates that pimelic acid is present in the exoquelin as a methyl ester. Based on this analysis, the general structure of the ferriexoquelines and the desferriexoquelines is shown in Figure 1. The methyl group shown in the R position, (as defined in Figure 10) can be in the R¿- position. The core molecule of iron exoquelin is circular with iron in the center. It contains 3 amino acid portions (two N-hydroxy-lysines and one serine or threonine, depending on whether R- is a hydrogen or methyl group). The main difference between exocoils and mycobactins from M. tuber-culosis is that R1 in the exholelines exists either as a saturated alkylmethyl ester ((CH JjrCOOCH) or an individually unsaturated alkylmethyl ester (CH2) CH = CH (CH2)? C00CH and the exocolelins have a much shorter alkyl side chain than the mycobactins with these shorter side chains terminating in methyl ester portions.These differences provide the solubility in water of the extrudes and their ability to function in the extracellular environment.
Clinical Utility - The clinical utility of administration of exocoils to prevent reperfusion injury was demonstrated by application to adult rat myocytes. In the following Examples, the different exo-lines will be identified, in the form of the desferri and ferri, by the molecular weight as shown in the elution curve in Figure 3.
Example 1 The heart of a male rat was excised after the rat was anesthetized, a thoracotomy was performed and the heart was refrigerated in situ. The excised heart was then placed in a Langendorff apparatus and perfumed with a collagenase and hyaluronidase in 50 μM calcium in a modified buffer solution of Krebs Ringer. The tissue was then finely divided and dispersed in a solution of collagenase / trypsin, filtered in a cold trypsin inhitoria solution and exposed to calcium-increasing concentrations. After removal of the damaged cells, the remaining cell suspension was placed in several plastic dishes coated with the inina together with a culture medium containing 5% fetal bovine serum. After they were allowed to settle the cultures for 4-8 hours, hydrogen peroxide was added to each of the dishes and the lactate dehydrogenase (LDH) activity, which is indicative of cell damage, was measured in several timeslots. A cell injury index (CII) was obtained for the purpose of comparison when measuring LDH in an unexposed cell culture, in a condition as it is (index 0) and the following exposure to a detergent that causes 100% lysis of the myocytes (1% of Triton X-100) representing a CU of 100. Then the LDH was determined under specific treatment conditions for various time periods, the corresponding CII value was determined and the individual results were exposed in a diagram against time (Figure 5). Using the procedure described above, a mixture of the desferri form of exo-lines 772C and 784 (a 50:50 mixture of peak 772C and peak 784-), a relatively non-polar substance, was isolated., and was used to treat cell cultures. The exoquelin was converted to the desferriexoquelin form by incubation for several days with 50 milli-molar EDTA at pH 6. The desferri form was then purified again by extraction with chloroform. Three samples of cells were exposed to either a) H2 ^ 2 '*) ^ 2 ^ 2 Y ^ ^ ^ e deferriexoquelin (iron-free exocole) added simultaneously or (c) HO added 2 hours after the addition of 100 μM of desferriexoquelien to the cell culture (prei? - ^ • cubation). The cultured untreated cell showed almost 62% cell damage over a period of 4 hours. In contrast to this, the addition of exoquelin simultaneously with, or 2 hours before, the addition of peroxide substantially prevented or significantly reduced cell damage, the cell injury is approximately 2 to 9%.
Example 2
The procedure of Example 1 was repeated with desferriexoquelin 758C which is relatively more polar than exo-lines 772C and 784-. There was little or no difference between the effect when the 753C desferriexoquelin was supplied together with or within 15 minutes of H? 0 ?. In both examples after 2 hours the cell destruction was substantially the same as in the control. However, the supply of the 753C deferrage 752C 2 hours before the introduction of H O cut the cell destruction to a CII of about 20. The results are shown in Figure 6.
3
The procedure set forth above was repeated using desferriexoquelin 772A, 772C and 758C. Exposed in a diagram in Figures 7-9 are the results for the pre-delivery of 2 hours, the simul- taneous supply and the delayed supply of 20 minutes of the exo-lines. Exo-sign 772C only shows the delay of the lesion under all conditions while the exo-line 772A is not effective under any conditions. On the other hand, the exoquelin 758C shows protection only if it is supplied 2 hours before the introduction of peroxide. Therefore, it is concluded that the relatively more non-polar lipid-soluble exo-lines are effective when administered with or after the radical formation (* 0H), that is, after the injury occurs; The most polar exo-lines should be administered 1 to 2 hours before the event where they generate free radicals to prevent or reduce cell destruction.
Example 4
The ability of the exocoils to compete for iron with host iron binding proteins is determined by incubation of desferriexoquelin with transferrin, lactoferrin or ferritin solutions at 4% 1 and 1: molar ratios of iron to exocole. The conversion of the exocole from its desferred form to its ferrous form is then determined by the reverse phase HPIC. In the space of one minute of exposition of the desfirriexoquelin to 95% of transferrin saturated with iron, the exoquelin had begun to recover the iron from the transferrin and in the space of one hour the exoquelin was completely saturated with iron. Iron was also easily removed from 4-0% transferrin saturated with iron, which approximates the level of iron in the transferrin as it exists in the serum. Similar results were obtained when the desferriexoquelina was exposed to lactoferrin saturated with iron. Similarly, ferritin released iron at exocole but at a slower rate than the other iron binding proteins. It has been discovered that exocoils are very effective in the collection of free iron in a physiological system and in removing iron from the iron carrier protein. In particular it has been found that exoquelin effectively blocks the formation of the hydroxyl-free radical (* 0H) and thus significantly reduces or prevents damage to the ischemic tissue when blood circulation to the tissue with the highest molecular weight is reestablished , less polar exo-lines are more effective in preventing cell destruction. While the benefit for cardiac tissue has been demonstrated, the benefit of the use of exo-lines followed by the interruption of blood flow to other organs of the body, including but not limited to the brain, kidney, liver, intestine, is now not apparent. skeletal muscle. The experimentation or test. has shown that the affinity of the exo-lines is not limited to iron but that other metals can be chelated, such as Na, K, Mn, Mg, Al and Zn. Therefore, exo-lines can be used to supply the body with various desirable metals or chelate various undesirable metals within the body. Additionally, certain cells, including certain cancer cells, are shown to be in need of, or affinity for, certain metals. This can be used to supply these compounds with cell reagents bound to the exo-lines for cell destruction (chemotherapy) or to target an internal organ with a beneficial drug bound to the exo-cellin. The other way, since certain cancer cells have a high demand for iron, the deferriexoquelines can be used to bind free iron, thus preventing the supply of iron to the cancer cell, resulting in the destruction of the cancer cell. While the structure of the exocoils recovered from M. tuberculosis is shown in Figure 1, it is known that another mycobacterium can generate exo-lines and that these exo-lines can have different structure and include different amino acids depending on the mycobacteria from which they have been released. However, all exo-lines will behave in a similar way and will exist in similar series with subsequent members thereof having a similar progression of molecular weights. The effectiveness of the different members of the series will also depend on the relative polarity of the molecules. Therefore, the invention contemplates exoquelines generated from other mycobacteria including, but not limited to M. tuberculosis, M. microti, M. bovis, M. africanum, M. kansasii, M. marinum, M. gastri, M. nonshromogenicum, M. terrae, M. trivale, M. malmoense, M. shimoidei, M. gordonae, M. asiaticum, M. szulgai, M. simiae, M. scrofulaceum, M. avium, M. intracellulare, M. xenopi, M. ulcerans, M. haemophilum, M. farcinogenes, M. lepraemurium, M. paratuberculosis, M. chelonae subsp. chelonae, M. chelonae subsp. abscessus, M. fortuitum, M. chitae, M. senegalense, M. agri, M. smegmatis, M. phlei, M. thermoresistibile, M. aichiense, M. aurum, M. chubuense, M. duvalii, M. flavescens, M. gadium. M. givum, M. komossense, M. neoaurum. M. obuense, M. parafortuitum. M. rhodesiae, M. sphagni, M. tokaiense or M. vaccae. It is also contemplated that the exo-lines can be modified to effect their solubility properties, metal chelating capacity or cellular absorption ratios. Additionally, the detection of modified exo-lines or exo-metal in their chelated metal state, using monoclonal antibodies or chemical analysis as diagnostic instruments, by means of blood analysis, urinalysis or urinalysis or non-invasive instrumental techniques, to monitor the progress of a disease status or treatment effectiveness. In particular, with reference to the structures of the metal-containing and metal-free compounds shown in Figure 10, the following substitutions are contemplated:
R .. = (OH JjjCH as a straight or branched chain; (CH2) COOH, a fatty acid; (CH2) COOR, a fatty acid ester where R is an alkyl group; (CH2) nC0NH2;
R? = a substitution at any of the 4 open ring sites of the alkyl, sulfonamide, hydroxyl, halogen, acetyl, carbamoyl, amines, N02 groups or any combination thereof;
- H (serine) or CH ^ (threonine) can be substituted by the side chains found in beta-hydroxy amino acids, which are capable of forming cyclic oxazoline structures.
R, and R ,, = H, CH, or other alkyl or substituted alkyl groups;
R5a and R5b ~ H > CH3 or alkyl or substituted alkyl groups;
X = O, NH, S, CH2;
M = mono-, di- or trivalent metals such as Pb, Al, Cf, Ni, Ag, Au, As, Mg, Mn, Zn, Cu, Ru, Nb, Zr, Ta, V, Ga, Pt, Cr, Se, Y, Co, Ti, Na, K;
* represents chiral centers which can be R or S;
The various hydroxyl (OH) groups involved in the formation of metal chelates can be substituted by various functional groups, such as H or a halogen, to vary the affinity of the compound for the chelated metal or to convert the molecule into a metal antagonist. . Although the present invention has been described in considerable detail with reference to certain preferred versions and uses thereof, other versions and uses are possible. For example, exo-lines can be used to attack infectious bacteria, such as M. tuberculosis, by blocking mycobacteria's access to iron, to remove toxic levels of metals from the body, or to supply desirable metals to the body. In addition, the modified metal containing exo-lines can supply drugs or active chemical substances attached to the cytos in the body, which preferentially absorb the chelated metal and the extruded ones preferentially absorbed with chelated metals can be used as targets for the treatment by other modalities, such as micro-wave energy for the treatment by hypothermia of cancer cells. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained herein.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, property is claimed as contained in the following:
Claims (11)
1. A method of protecting living tissue in a mammal from injury resulting from exposure to the hydroxyl free radical formed after reestablishment of fluid flow to an organ of the body after restriction of blood flow to this body organ, characterized because it comprises administering a composition containing an effective amount of a deferriexoquelin to the mammal in conjunction with the reestablishment of fluid flow to the tissue.
2. The method according to claim 1, characterized in that the desferriexoque-lines are administered before the administration of the fluid.
3. The method according to claim 1, characterized in that the deferriexoquelines are administered at least as soon as the time of administration of the fluid begins.
4. . The method according to claim 1, characterized in that the desferriexoquelin is administered within approximately fifteen minutes after the start of fluid administration.
5. The method according to claim 1, characterized in that the living tissue is myocardium and the fluid is selected from the group consisting of reperfusion solution and cario-plesi solution.
6. The method according to claim 1, characterized in that the composition contains an effective amount of at least one desferriexoquelin which has the formula: where R-. is selected from the group consisting of (CH2) NC00CH3 and (CH2)? CH = CH (CH2)? C00CH3 with N which is from 1 to 7 and x + y is from 1 to 5 and is selected from the group consisting of H and CH.-, is selected of the group consisting of H and CH ^, the deferriexoquelines having a molecular weight from about 716 to about 826 daltons.
7. The method according to claim 6, characterized in that the composition includes a mixture of desferriexoquelines having a molecular weight of 772 and 784-daltons.
8. The method according to claim 6, characterized in that the composition includes a mixture of relatively non-polar deferriexoquelines, characterized in that N is an integer from 5 to 7.
9. The method according to claim 6, characterized in that the composition includes a mixture of relatively polar deferriexoquelines characterized in that x + y is 4 a or 5.
10. A composition for preventing • injury to living tissue of a mammal in the presence of iron-mediated hydroxyl radical formation, characterized in that it comprises an effective amount of at least one desferriexoquelin having the formula: where R .. is selected from the group consisting of (CH2) NC00CH3 and (CH2) NCH = CH (CH2)? C00CH3 with N which is from 7 and x + y which is from 1 to 5 and R, is selected from group consisting of H and CH ^ the deferriexoquelines having a molecular weight of about 716 to about 826 daltons.
11. A composition for delivering effective amounts of an active compound to a mammal to treat a medical condition, the composition is characterized in that it has the formula: 10 wherein R .. is a chemical moiety selected from the group consisting of (CH2) nCH, (CH2) nC00H, 15 (CH2) nC00R where R is an alkyl group and (CH2) nC0NH2; R2 is a substituted chemical moiety in any of the 4 open sites in the ring, the chemical portion is selected from the group 20 which consists of alkyl, sulfonamide, hydroxyl, halogen, acetyl, carbamyl, amines and N02 groups and combinations thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/383,180 US5721209A (en) | 1995-02-03 | 1995-02-03 | Iron chelator and inhibitor of iron-mediated oxidant injury |
US08383180 | 1995-02-03 |
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MX9604499A MX9604499A (en) | 1997-11-29 |
MXPA96004499A true MXPA96004499A (en) | 1998-07-03 |
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