NO‐Dismutase‐Aktivität siebenfach koordinierter Mangan(II)‐ Komplexe von Pentaazamakrocyclen

Filipović, Miloš R.; Duerr, Katharina; Mojović, Miloš; Simeunović, Vladica; Zimmermann, Robert A.; Niketić, Vesna

doi:10.1002/ange.200801325

“…and ONOO − releases. This study thus demonstrates that the previously established in vitro chemistry of the SOD mimics used here5b is valid in vivo as well, thus leading to a rare example where in vitro chemistry explains very well in vivo effects.…”

Section: Methodssupporting

confidence: 62%

“…However, drawing an analogy with native enzyme,5a some of us have recently shown that such complexes do react with NO . , albeit at lower rates than with O 2 .− (the rate constant for aerobic reaction with NO was estimated to be 850 M −1 s −1 , whereas the catalytic rate constant for O 2 .− dismutation is 1×10 7 M −1 s −1 ) 5b. We proposed a new dismutation mechanism which involves the formation of labile metal–nitrosyl complexes and leads to the catalytic removal of large amounts of NO .…”

Section: Methodsmentioning

confidence: 90%

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Striking Inflammation from Both Sides: Manganese(II) Pentaazamacrocyclic SOD Mimics Act Also as Nitric Oxide Dismutases: A Single‐Cell Study

Filipović

¹

,

Koh

²

,

Arbault

³

et al. 2010

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During the course of an inflammatory response, nitric oxide (NOC; formed by inducible NO synthase, iNOS) and superoxide (O 2 C À ; formed by NADPH oxidase or NOX2) are both generated in quantities that surpass physiological levels. [1] Consecutively, NOC and O 2 C À react at a diffusion-controlled rate (k % 10 10 m À1 s À1 ) to form peroxynitrite (ONOO À ) and other reactive species (such as NO 2 C and OHC), which induce cytotoxic effects through DNA damage, low-density lipoprotein oxidation, protein nitration and oxidation, aconitase inactivation, and inhibition of respiration.[2] Several attempts have been made to either inhibit NOC production, by designing selective iNOS inhibitors, [3a] or to mimic the activity of superoxide dismutase (SOD), by developing low-molecularweight metal complexes, [3b] to treat diseases characterized by hyperinflammation. However, the pharmacological application of iNOS inhibitors [3c] or SOD mimics [3d] is restricted by a certain lack of selectivity, stability, and/or bioavailability of these compounds. Mn II pentaazamacrocyclic complexes feature the presently most potent synthetic SOD mimics. They were discovered just a decade ago [4a] and have since entered phase II clinical trials in the USA.[4b] Their main advantage is reported to be a strict selectivity towards superoxide.[ ).[5b] We proposed a new dismutation mechanism which involves the formation of labile metal-nitrosyl complexes and leads to the catalytic removal of large amounts of NOC from solution [5b] [Eqs. (1) and (2)]. Therefore, this class of complexes might also act towards NOC generation during an inflammatory response.To clarify the pharmacological effects related to the chemistry of Mn II pentaazamacrocyclic SOD mimics, we used [Mn II (pyane)Cl 2 ] (Scheme 1) [6] as a general representative of this class of complexes and studied its effect on the production of O 2 C À and NOC by living cells.Macrophages are the main actors in the production of reactive oxygen (ROS) and reactive nitrogen (RNS) species in inflammation, [7] so they were selected as cell models in this study. Moreover, some of us have shown that electrochemistry at ultramicroelectrodes offers the unique possibility of in situ, real-time, and direct measurements of ROS and RNS generated by cells, including species that are short-lived like ONOO À .[8] Thus, the ROS/RNS production by single immu-

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“…Besides removing superoxide, SOD mimetics may react with other ROS, which include hydrogen peroxide, peroxynitrite, carbonate radicals, peroxyl radicals, and alkoxyl radicals . SOD mimetics also react with reactive nitrogen species, which include nitric oxide . SOD mimetics, which generate additional hydrogen peroxide as a by‐product of the dismutation reaction, may decrease cell proliferation and enhance chemotherapy and radiotherapy treatment efficacy in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

Bonetta

¹

2017

Chemistry A European J

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Natural as well as synthetic antioxidants are constantly being investigated for their efficiency in combatting the effects of oxidative stress, which appears to be the responsible cause of several diseases, including cancer, central nervous system disorders, ischaemia-reperfusion disorders, cardiovascular conditions, and diabetes. Superoxide dismutases (SODs) constitute the ubiquitous antioxidant defences against oxidative stress that underlies numerous pathological conditions. Therefore, the development of therapeutics aimed at either delivering MnSOD more effectively to target tissues in the body in the form of MnSOD gene therapy, or the synthesis of molecules that mimic the activity of superoxide dismutase is constantly being explored. Classes that have been developed as SOD mimetics include the Mn-metalloporphyrins, Mn-cyclic polyamines, Mn-salen complexes, MnPLED derivatives as well as the nitroxides. Thus far, SOD mimetics have shown remarkable efficacy in several animal models suffering from oxidative stress injuries. A promising approach for the future of SOD and SOD mimic therapeutics appears to involve combination treatment of the antioxidants with radiotherapy or chemotherapy.

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Striking Inflammation from Both Sides: Manganese(II) Pentaazamacrocyclic SOD Mimics Act Also as Nitric Oxide Dismutases: A Single‐Cell Study

Filipović

¹

,

Koh

²

,

Arbault

³

et al. 2010

View full text Add to dashboard Cite

During the course of an inflammatory response, nitric oxide (NOC; formed by inducible NO synthase, iNOS) and superoxide (O 2 C À ; formed by NADPH oxidase or NOX2) are both generated in quantities that surpass physiological levels. [1] Consecutively, NOC and O 2 C À react at a diffusion-controlled rate (k % 10 10 m À1 s À1 ) to form peroxynitrite (ONOO À ) and other reactive species (such as NO 2 C and OHC), which induce cytotoxic effects through DNA damage, low-density lipoprotein oxidation, protein nitration and oxidation, aconitase inactivation, and inhibition of respiration.[2] Several attempts have been made to either inhibit NOC production, by designing selective iNOS inhibitors, [3a] or to mimic the activity of superoxide dismutase (SOD), by developing low-molecularweight metal complexes, [3b] to treat diseases characterized by hyperinflammation. However, the pharmacological application of iNOS inhibitors [3c] or SOD mimics [3d] is restricted by a certain lack of selectivity, stability, and/or bioavailability of these compounds. Mn II pentaazamacrocyclic complexes feature the presently most potent synthetic SOD mimics. They were discovered just a decade ago [4a] and have since entered phase II clinical trials in the USA.[4b] Their main advantage is reported to be a strict selectivity towards superoxide.[ ).[5b] We proposed a new dismutation mechanism which involves the formation of labile metal-nitrosyl complexes and leads to the catalytic removal of large amounts of NOC from solution [5b] [Eqs. (1) and (2)]. Therefore, this class of complexes might also act towards NOC generation during an inflammatory response.To clarify the pharmacological effects related to the chemistry of Mn II pentaazamacrocyclic SOD mimics, we used [Mn II (pyane)Cl 2 ] (Scheme 1) [6] as a general representative of this class of complexes and studied its effect on the production of O 2 C À and NOC by living cells.Macrophages are the main actors in the production of reactive oxygen (ROS) and reactive nitrogen (RNS) species in inflammation, [7] so they were selected as cell models in this study. Moreover, some of us have shown that electrochemistry at ultramicroelectrodes offers the unique possibility of in situ, real-time, and direct measurements of ROS and RNS generated by cells, including species that are short-lived like ONOO À .[8] Thus, the ROS/RNS production by single immu-

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NO‐Dismutase‐Aktivität siebenfach koordinierter Mangan(II)‐ Komplexe von Pentaazamakrocyclen

Cited by 3 publications

References 29 publications

Striking Inflammation from Both Sides: Manganese(II) Pentaazamacrocyclic SOD Mimics Act Also as Nitric Oxide Dismutases: A Single‐Cell Study

Striking Inflammation from Both Sides: Manganese(II) Pentaazamacrocyclic SOD Mimics Act Also as Nitric Oxide Dismutases: A Single‐Cell Study

Potential Therapeutic Applications of MnSODs and SOD‐Mimetics

Striking Inflammation from Both Sides: Manganese(II) Pentaazamacrocyclic SOD Mimics Act Also as Nitric Oxide Dismutases: A Single‐Cell Study

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