Rings of Power: Controlling SOD Mimic Activity by the Addition of Pyridine Rings within the Pyridinophane Scaffold

IF 4.3 2区 化学 Q1 CHEMISTRY, INORGANIC & NUCLEAR
Katherine J. Smith, Timothy M. Schwartz, David M. Freire, Cameron J. Bowers, Sarah K. Dunn, Jackson F. Bonnell, Magy A. Mekhail, Giridhar Akkaraju, Kayla N. Green
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Abstract

Superoxide dismutase enzymes are a major defense against superoxide, which is a potent reactive oxygen species. Misregulation of reactive oxygen species and subsequent neuronal damage are etiological hallmarks of neurodegenerative disease. Macrocyclic small molecules have offered inroads toward functional SOD1 mimics. Herein, we report a series of five tetra-aza macrocyclic RPy2N2 ligands, varied by 4-position substitution of the pyridine ring with both electron-donating (R = OMe) and withdrawing groups (R = Cl, I, and CF3) to offer the first comparison to well-studied RPyN3 congeners and other mimics in the literature. New ligands have been characterized by NMR, mass spectrometry, elemental analysis, and potentiometric titrations (pKa). Cyclic voltammetry and X-ray diffraction analysis of the copper(II) complexes (CuII(RPy2N2)2+) demonstrate how pyridine substitution impacts the metal center. This data, and evaluation of the log βCu(II) and log βCu(I) within the series, indicates significant improvement to the binding affinity for Cu(I) without sacrifice of Cu(II) binding. The CuII(RPy2N2)2+ series yield the highest kcat for any Cu(II)-based small molecule functional SOD1 mimic (kcat = 45.36 M–1 s–1). Furthermore, the CuII(OMePy2N2)2+ and CuII(CF3Py2N2)2+ complexes were studied in FRDA cells to determine cell toxicity as a first step toward the application of these mimics as therapeutics for neurological disease.

Abstract Image

功率环:通过在吡啶支架内添加吡啶环来控制SOD模拟活性
超氧化物歧化酶是对抗超氧化物的主要防御物质,超氧化物是一种有效的活性氧。活性氧的错误调节和随后的神经元损伤是神经退行性疾病的病因学标志。大环小分子为功能性SOD1模拟物提供了突破口。本文中,我们报道了一系列的五种四氮杂大环RPy2N2配体,它们通过吡啶环上的给电子基团(R = OMe)和撤回基团(R = Cl, I和CF3)的4位取代而变化,首次与文献中研究得很好的RPyN3同族化合物和其他类似物进行了比较。新的配体已经通过核磁共振、质谱、元素分析和电位滴定(pKa)进行了表征。铜(II)配合物(CuII(RPy2N2)2+)的循环伏安法和x射线衍射分析证明了吡啶取代对金属中心的影响。该数据以及对该系列中对数βCu(II)和对数βCu(I)的评价表明,在不牺牲Cu(II)结合的情况下,对Cu(I)的结合亲和力有显著提高。CuII(RPy2N2)2+系列对Cu(II)基小分子功能SOD1模拟物的kcat值最高(kcat = 45.36 M-1 s-1)。此外,在FRDA细胞中研究了CuII(OMePy2N2)2+和CuII(CF3Py2N2)2+复合物,以确定细胞毒性,这是将这些模拟物应用于神经系统疾病治疗的第一步。
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来源期刊
Inorganic Chemistry
Inorganic Chemistry 化学-无机化学与核化学
CiteScore
7.60
自引率
13.00%
发文量
1960
审稿时长
1.9 months
期刊介绍: Inorganic Chemistry publishes fundamental studies in all phases of inorganic chemistry. Coverage includes experimental and theoretical reports on quantitative studies of structure and thermodynamics, kinetics, mechanisms of inorganic reactions, bioinorganic chemistry, and relevant aspects of organometallic chemistry, solid-state phenomena, and chemical bonding theory. Emphasis is placed on the synthesis, structure, thermodynamics, reactivity, spectroscopy, and bonding properties of significant new and known compounds.
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