ES2569239T3 - Complejos metálicos miméticos de SOD - Google Patents
Complejos metálicos miméticos de SOD Download PDFInfo
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- ES2569239T3 ES2569239T3 ES10816744.6T ES10816744T ES2569239T3 ES 2569239 T3 ES2569239 T3 ES 2569239T3 ES 10816744 T ES10816744 T ES 10816744T ES 2569239 T3 ES2569239 T3 ES 2569239T3
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- sod
- metal complexes
- polyazapyridinophane
- superoxide dismutase
- macrocyclic
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- 229910052751 metal Inorganic materials 0.000 title abstract description 5
- 239000002184 metal Substances 0.000 title abstract description 5
- 102000019197 Superoxide Dismutase Human genes 0.000 abstract description 23
- 108010012715 Superoxide dismutase Proteins 0.000 abstract description 23
- 239000003963 antioxidant agent Substances 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 150000002678 macrocyclic compounds Chemical class 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 230000005856 abnormality Effects 0.000 abstract description 2
- 230000001760 anti-analgesic effect Effects 0.000 abstract description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 230000008809 cell oxidative stress Effects 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 150000002736 metal compounds Chemical class 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 7
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 5
- 102000008221 Superoxide Dismutase-1 Human genes 0.000 description 5
- 102100032891 Superoxide dismutase [Mn], mitochondrial Human genes 0.000 description 5
- 102100027186 Extracellular superoxide dismutase [Cu-Zn] Human genes 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 108010045815 superoxide dismutase 2 Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- 101000836222 Homo sapiens Extracellular superoxide dismutase [Cu-Zn] Proteins 0.000 description 3
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 208000001300 Perinatal Death Diseases 0.000 description 2
- 101710149951 Protein Tat Proteins 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 231100000225 lethality Toxicity 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 210000000651 myofibroblast Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910002535 CuZn Inorganic materials 0.000 description 1
- 108700001268 Extracellular superoxide dismutase [Cu-Zn] Proteins 0.000 description 1
- 208000025500 Hutchinson-Gilford progeria syndrome Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 108700005084 Multigene Family Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000007932 Progeria Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 1
- 101710119418 Superoxide dismutase [Mn] Proteins 0.000 description 1
- 101710202572 Superoxide dismutase [Mn], mitochondrial Proteins 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000006851 antioxidant defense Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000007323 disproportionation reaction Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 230000004730 hepatocarcinogenesis Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000037891 myocardial injury Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- CMFNMSMUKZHDEY-UHFFFAOYSA-N peroxynitrous acid Chemical compound OON=O CMFNMSMUKZHDEY-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G47/00—Compounds of rhenium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La presente invención comprende un procedimiento para sintetizar complejos metálicos a partir de compuestos macrocíclicos poliazapiridinofanos,caracterizados por ser miméticos de la enzima superóxido dismutasa (SOD). Además la presente invención hace referencia a los propios compuestos metálicos macrocíclicos poliazapiridinofanos, a los complejos metálicos formados a partir de ellos y al uso de éstos en terapia para el tratamiento de enfermedades cuya etiología se basa en anomalías de la actividad de la SOD endógena, principalmente como antiinflamatorios, analgésicos y antioxidantes protectores del estrés oxidativo celular.
Description
Descripción
5 La presente invención comprende un procedimiento para sintetizar complejos metálicos, a partir de compuestos macrocíclicos poliazapiridinofanos, caracterizados por ser miméticos de la enzima superóxido dismutasa (SOD). Además, la presente invención hace referencia a los propios compuestos macrocíclicos poliazapiridinofanos, a los complejos metálicos formados a partir de ellos y al uso de éstos en terapia para el tratamiento de enfermedades cuya etiología se basa en anomalías de la actividad o carencia de la SOD endógena, principalmente como antiinflamatorios, analgésicos y antioxidantes protectores del estrés oxidativo celular.
La reacción de dismutación del radical superóxido (O2-) en oxígeno y peróxido de hidrógeno (H2O2), catalizada por la
15 enzima SOD, convierte a dicha enzima en una importante defensa antioxidante para la mayoría de las células expuestas al oxígeno. Así, la SOD protege a la célula de las reacciones dañinas del radical O2-. En humanos existen tres formas de SOD. SOD1 se encuentra en el citoplasma, en compartimentos nucleares y en el espacio intermembrana de la mitocondria. SOD2 se encuentra en las mitocondrias y SOD3 en el líquido extracelular. La primera es un dímero (consiste en dos subunidades), mientras que las otras son tetrámeros (cuatro subunidades). SOD1 y SOD3 contienen cobre y zinc, mientras que SOD2 tiene manganeso en su centro reactivo.
La importancia fisiológica de la SOD es ilustrada por las severas patologías que se evidencian en ratones genéticamente modificados para que carezcan de esta enzima y por la reversión de dichas patologías cuando se aplica una SOD externa a los pacientes.
25 Las mutaciones en SOD1 se han relacionado con la esclerosis lateral amiotrófica (ELA) y su inactivación con el desarrollo de hepatocarcinomas [Elchuri, et al., S. (2005). CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in lif. Oncogene 24: 367-380]. Además, los ratones sin SOD1 exhiben una acelerada pérdida de masa muscular relacionada con la edad [Muller, et al., F. L. (2006). Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic. Biol. Med 40: 1993-2004], una temprana incidencia de cataratas y una esperanza de vida reducida.
En ratones, la inactivación de SOD2 provoca la muerte perinatal y su carencia provoca la muerte de los ratones a los pocos días de nacer por estrés oxidativo masivo [Li, et al., Y. (1995). Dilated cardiomyopathy and neonatal lethality in
35 mutant mice lacking manganese superoxide dismutase. Nat. Genet. 11: 376-381].
Así, existen numerosas enfermedades relacionadas con la presencia del anión superóxido y la carencia o disfunción de la SOD endógena entre las que se encuentran, a modo de ejemplo, enfermedades inflamatorias como la artritis reumatoide, la osteoartritis, enfermedad de Chron, enfermedad de Parkinson, varios tipos de cáncer, enfermedad de Alzheimer, diabetes, fibrosis, psoriasis, asma, etc. [Maritim AC et al., (2003), Diabetes. Oxidative stress and antioxidants: a review, J. Biochem. Mol. Toxicol, 17: 24-38].
Por otro lado, la SOD es usada en productos cosméticos para reducir el daño de los radicales libres a la piel, por ejemplo, para reducir la fibrosis que se produce como consecuencia de la radioterapia. Se sabe que la SOD revierte la 45 fibrosis [Vozenin-Brotons, MC. et al. (2001). Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts. Free Radic Biol Med. 30 (1): 30–42. PMID 11134893] posiblemente a través de la reversión de los miofibroblastos de nuevo a fibroblastos. Además la SOD es usada para el tratamiento del dolor y de los efectos de la quimioterapia y la radiación [Lebovitz, et al. (1996) Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide-deficient mice. Proc. Natl. Acad. Sci. USA. 93: 9782-9787], [Li et al (1995). Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganeso superoxide dismutase. Nat. Genet. 11: 376381], [Zelko et al (2002) Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2) and EC-SOD (SOD3) gene structures, evolution and expression. Free Radic. Biol. Med. 33:337-349]; [Chen et al. (1998) Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. J. Mol. Cell. Cardiol. 30:2281-2289], [Keller, et al. (1998) Mitochondrial manganese superoxide dismutase prevents neural
55 apoptosis and reduces ischemic brain injury suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction, J. Neurosc. 18:687-697]; [Flores et al. (1993) Tat protein of human immunodeficiency virus type 1 represses expression of manganeso superoxide dismutase in HeLa cells, Proc. Natl. Acad. Sci. USA, 90:7632-7636]; [Westendorp et al (1995) HIV-1 Tat pontentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state, Embo. J., 14:546-554], [Yan (1999) Altered levels of primary antioxidant enzymes in progeria skim fibroblasts, Biochem. Biophys. Res. Commun., 257:163-167].
Los cambios en las constantes de equilibrio de protonación y la formación de complejos de CuII se han analizado y comparado con la poliamina no cíclica 232 y tres ciclofanos (o-, m- y p-B232). La estabilidad de los complejos de CuII a través de los restos amina es distinta para cada ciclofano y, por lo tanto, su capacidad para formar complejos 65 mononucleares y dinucleares y su comportamiento cinético también son distintos para cada compuesto. [Verdejo B et al.
2
Claims (1)
-
imagen1 imagen2
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200930712A ES2355784B1 (es) | 2009-09-21 | 2009-09-21 | Complejos metalicos mimeticos de sod |
| ES200930712 | 2009-09-21 | ||
| PCT/ES2010/070607 WO2011033163A2 (es) | 2009-09-21 | 2010-09-20 | Complejos metálicos miméticos de sod |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2569239T3 true ES2569239T3 (es) | 2016-05-09 |
Family
ID=43736319
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200930712A Active ES2355784B1 (es) | 2009-09-21 | 2009-09-21 | Complejos metalicos mimeticos de sod |
| ES10816744.6T Active ES2569239T3 (es) | 2009-09-21 | 2010-09-20 | Complejos metálicos miméticos de SOD |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200930712A Active ES2355784B1 (es) | 2009-09-21 | 2009-09-21 | Complejos metalicos mimeticos de sod |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US9145386B2 (es) |
| EP (1) | EP2492270B1 (es) |
| ES (2) | ES2355784B1 (es) |
| WO (1) | WO2011033163A2 (es) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2414291B2 (es) * | 2011-12-16 | 2014-02-13 | Universitat De Valencia | Compuestos macrocíclicos de tipo escorpiando y su uso como antiparasitarios. |
| ES2543850B1 (es) * | 2014-02-24 | 2016-06-16 | Universitat De Valencia | Uso de complejos metálicos miméticos de SOD como agentes alimentarios y como cosméticos |
| WO2019007996A1 (en) | 2017-07-04 | 2019-01-10 | Bionos Biotech, S.L | USE OF METALLIC COMPLEXES OF MACROAZAPYRIDINOPHANES IN THE TREATMENT OF DISEASES |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6794371B1 (en) * | 1999-10-18 | 2004-09-21 | The Dow Chemical Company | Aminoalkylenephosphonates for treatment of bone disorders |
| CA2436245C (en) * | 2001-01-19 | 2013-04-23 | National Jewish Medical And Research Center | Medicament for protection in radiotherapy |
| AU2002312194B8 (en) * | 2001-06-01 | 2008-05-15 | Aeolus Sciences, Inc. | Oxidant scavengers for treatment of diabetes or use in transplantation or induction of immune tolerance |
| US8128688B2 (en) * | 2006-06-27 | 2012-03-06 | Abbott Cardiovascular Systems Inc. | Carbon coating on an implantable device |
-
2009
- 2009-09-21 ES ES200930712A patent/ES2355784B1/es active Active
-
2010
- 2010-09-20 ES ES10816744.6T patent/ES2569239T3/es active Active
- 2010-09-20 WO PCT/ES2010/070607 patent/WO2011033163A2/es active Application Filing
- 2010-09-20 US US13/497,135 patent/US9145386B2/en active Active
- 2010-09-20 EP EP10816744.6A patent/EP2492270B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011033163A3 (es) | 2011-07-07 |
| ES2355784B1 (es) | 2012-02-03 |
| WO2011033163A2 (es) | 2011-03-24 |
| EP2492270A4 (en) | 2013-01-16 |
| US9145386B2 (en) | 2015-09-29 |
| EP2492270B1 (en) | 2016-03-09 |
| ES2355784A1 (es) | 2011-03-31 |
| EP2492270A2 (en) | 2012-08-29 |
| US20120178730A1 (en) | 2012-07-12 |
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