Redox Potential of Nitroxides is an Index to Evaluate Superoxide Dismutase Mimic Activity
Redox Potential of Nitroxides is an Index to Evaluate Superoxide Dismutase Mimic Activity
复制标题
DOI：
10.1002/ajoc.201300011
复制
发表时间：
2013-05-01
影响因子：
2.7
通讯作者：
Yamada, Ken-ichi
中科院分区：
文献类型：
--
作者：
Yamasaki, Toshihide;Matsuoka, Yuta;Yamada, Ken-ichi
超氧化物导致动物和人类氧化还原失衡和氧化应激疾病。[1]尽管超氧化物歧化酶（SOD）在体内发挥着重要作用，但由于其生物利用度低，SOD不适合临床应用。因此，非常需要开发低分子量SOD模拟物来治疗超氧化物相关病症。一组候选者是氮氧化合物，有机自旋化合物，由于其与自由基反应的能力而被用作抗氧化剂。[2]例如，4-羟基-2，2，6，6-四甲基哌啶-1-氧基（Tempol; 1，表1）具有良好的SOD模拟活性[3]，并且已经进行了临床试验。[4]超氧化物和氮氧化物之间的反应机理取决于氮氧化物/N-氧代铵阳离子对的氧化还原电位。为了对超氧化物更具反应性，氮氧自由基倾向于需要较低的氧化还原电位。[5]氮氧化物的氧化还原电位随取代基而变化，例如，在哌啶环的4-位。[6]在此，我们描述了改变C4位（表1中的R1和R2）上的取代基对氮氧化合物的氧化还原电位的影响，目的是确定用于开发更好的SOD模拟物的良好指标。我们合成了新的氮氧化合物6-12，以与市售氮氧化合物1-5（表1）比较在C4位取代氢原子和氧化还原电位对SOD模拟活性的影响。我们首先以2，2，6，6-四甲基-4-哌啶酮和各种醇或硫醇衍生物为原料，在对甲苯磺酸的促进下，通过缩酮或缩硫酮的生成反应合成了6-12的哌啶前体化合物。然后用过氧化氢和钨酸钠氧化相应的哌啶合成氮氧自由基。在该氧化中，硫化物基团被完全氧化成砜。在磷酸盐缓冲液（PB，pH7.4）中，用玻碳电极循环伏安法测定了氮氧自由基的氧化还原电位。氮氧自由基发生单电子氧化，相当于在与O2·OH自由基的氧化还原反应中形成N-氧代铵阳离子;换句话说，氮氧自由基还原超氧化物。因此，氧化还原电位较低的氮氧化物与O2·OH的反应性较高。1-12的单电子氧化还原对的氧化还原电势列于表2中。已知1-4在PB中的氧化还原电位E1/2与以前报道的数据一致。除2-4外，1-12的峰分离，ΔE= EpaEpc，为58- 70 mV，接近理论能斯特值59 mV。此外，阳极和阴极电流的强度，除了2和3，几乎相等。这些氮氧化物的伏安分析显示，在正电位的单电子氧化还原对。此外，1-12的氧化还原电位根据C4位上的取代基的类型而变化。特别地，在螺环中具有磺酰基取代的8、9、11和12由于吸电子效应而具有更高的电势值。这一结果与我们以前报道的氮氧化合物的性质一致（约。1.07 V vs.标准氢电极，SHE），其在哌啶衍生物的C2和C6位的螺环中也具有磺酰基。[7]相比之下，没有氮氧化物具有比Tempol更低的氧化还原电位，除了4。[a]T医生Yamasaki，Y. Matsuoka，F.水户，K医生- I.九州大学药学部山田生物机能学研究科福冈市东区3-1-1邮编：812-8582传真：（+ 81）92-642-6626
Superoxide causes redox imbalance and oxidative stress diseases in animals and humans.[1] Although the superoxide dismutase (SOD) enzyme plays an important role in vivo, SOD is unsuitable for clinical applications because of the low bioavailability of the enzyme. Therefore, there is a significant need to develop low molecular weight SOD mimics to treat superoxide relevant disorders. One group of candidates is nitroxides, organic spin compounds, which has been used as an antioxidant because of its ability to react with free radicals.[2] For example, 4-hydroxy-2, 2, 6, 6-tetramethylpiperidin-1-oxyl(Tempol; 1, Table 1) has good SOD mimetic activity [3] and has undergone clinical trials.[4] The mechanism of the reaction between superoxide and nitroxide is dependent on the redox potential of the nitroxide/N-oxoammonium cation couple. To be more reactive toward superoxide, nitroxides tend to require a lower redox potential.[5] The redox potentials of nitroxides vary with the substituents, for example, at the 4-position of the piperidine ring.[6] Herein, we describe the effect of varying the substituents at the C4 position (R1 and R2 in Table 1) on the redox potential of nitroxides with the aim of identifying a good index for developing a better SOD mimic. We synthesized the new nitroxides 6–12 to compare the effect of substituting the hydrogen atom at the C4 position and the redox potentials on SOD-mimicking activity with commercially available nitroxides 1–5 (Table 1). We first synthesized the precursor piperidine compounds of 6–12 from 2, 2, 6, 6-tetramethyl-4-piperidone and each alcohol or thiol derivative by using a ketal-or thioketal-forming reaction promoted by ptoluenesulfonic acid. Then the nitroxides were synthesized by oxidation of the corresponding piperidine by using hydrogen peroxide and sodium tungstate. In this oxidation, sulfide groups were completely oxidized to sulfones. The redox potentials of the nitroxides were determined by cyclic voltammetry in phosphate buffer (PB, pH 7.4) by using a glassy carbon electrode. Nitroxides undergo oneelectron oxidation that corresponds to the formation of an N-oxoammonium cation in the redox reaction with O2· À radicals; in other words, the nitroxide reduces the superoxide. Therefore, the reactivity with O2· À is assumed to be higher for nitroxides that have a lower redox potential. The redox potentials of the one-electron redox couple for 1–12 are listed in Table 2. The redox potentials, E1/2, of known 1–4 in PB were in agreement with the previously reported data. The peak separation, ΔE= EpaÀEpc, of 1–12, except for 2–4, was 58–70mV, which is close to the theoretical Nernstian value of 59 mV. Furthermore, the intensities of the anodic and cathodic currents, except for 2 and 3, were almost equal. Voltammetric analysis of these nitroxides revealed a one-electron redox couple at positive potentials. Furthermore, the redox potentials of 1–12 vary according to the type of substituent at the C4 position. In particular, 8, 9, 11, and 12, which have sulfonyl group (s) substituted in the spiro ring, have higher potential values because of the electron-withdrawing effect. This result is consistent with the properties of our previously reported nitroxide (ca. 1.07 V vs. standard hydrogen electrode, SHE), which also has the sulfonyl group in spiro ring at the C2 and C6 positions of a piperidine derivative.[7] In contrast, no nitroxides had a lower redox potential than Tempol, except for 4.[a] Dr. T. Yamasaki, Y. Matsuoka, F. Mito, Dr. K.-i. Yamada Department of Bio-functional Science Faculty of Pharmaceutical Sciences Kyushu University 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582 (Japan) Fax:(+ 81) 92-642-6626