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
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DOI：
10.1002/anie.200905936
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Ivanovic-Burmazovic, Ivana
中科院分区：
文献类型：
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作者：
Filipovic, Milos R.;Koh, Alaric C. W.;Ivanovic-Burmazovic, Ivana
在炎症反应过程中，一氧化氮(NOC；由诱导型一氧化氮合酶(INOS)形成)和超氧化物歧化酶(O2C；[1]NOC和O2C以扩散控制的速度(k%1010m±1 S±1)反应生成过氧亚硝酸盐(ONOO±)和其他活性物种(如NO2C和OHC)，这些反应通过dna损伤、低密度脂蛋白氧化、蛋白质硝化和氧化、乌头酸酶失活和呼吸抑制来诱导细胞毒效应。[2]人们已经进行了几种尝试，要么通过设计选择性的iNOS抑制剂来抑制NOC的产生，[3a]，要么通过开发低分子量金属络合物来模拟超氧化物歧化酶的活性。[3B]治疗以过度炎症为特征的疾病。然而，诱导型一氧化氮合酶抑制剂[3c]或超氧化物歧化酶模拟物[3D]的药理应用受到这些化合物缺乏选择性、稳定性和/或生物利用度的限制。它们在十年前才被发现[4a]，并已在美国进入第二阶段临床试验。[4b]据报道，它们的主要优势是对超氧化物的严格选择性。[4a-e]然而，通过与天然酶的类比，[5a]我们中的一些人最近已经证明，这种复合体确实与NOC反应，尽管速度低于O2C±(与NO的好氧反应的速率常数估计为850m±1 S±1，而O2C的催化速率常数为1107m±1 S±1)。[5B]我们提出了一种新的歧化机理，它涉及不稳定的金属-亚硝基络合物的形成，并导致催化脱除溶液中的大量NOC[式(1)和(2)]。因此，这类复合体也可能在炎症反应过程中促进NOC的产生。
During the course of an inflammatory response, nitric oxide (NOC; formed by inducible NO synthase, iNOS) and superoxide (O2C À; formed by NADPH oxidase or NOX2) are both generated in quantities that surpass physiological levels.[1] Consecutively, NOC and O2C À react at a diffusion-controlled rate (k% 1010 m À1 sÀ1) to form peroxynitrite (ONOOÀ) and other reactive species (such as NO2C 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.MnII 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.[4a–e] However, drawing an analogy with native enzyme,[5a] some of us have recently shown that such complexes do react with NOC, albeit at lower rates than with O2C À (the rate constant for aerobic reaction with NO was estimated to be 850mÀ1 sÀ1, whereas the catalytic rate constant for O2C À dismutation is 1 107 m À1 sÀ1).[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.