4,7-二羟基香豆素衍生物对产生 ROS 的酶的抑制潜力和直接清除 HOO-/o2- 自由基的活性--一项全面的动力学 DFT 研究。

IF 3.6 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Žiko Milanović,Svetlana Jeremić,Marko Antonijević,Dušan Dimić,Đura Nakarada,Edina Avdović,Zoran Marković
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引用次数: 0

摘要

本研究考察了三种合成香豆素衍生物的抗自由基活性:(E)-3-(1-((2-羟基苯基)氨基)亚乙基)-2,4-二氧二苯并二氢吡喃-7-基乙酸酯(A1-OH)、(E)-3-(1-((3-羟基苯基)氨基)亚乙基)-2、4-二氧二苯并二氢吡喃-7-基乙酸酯(A2-OH)和(E)-3-(1-((4-羟基苯基)氨基)亚乙基)-2,4-二氧二苯并二氢吡喃-7-基乙酸酯(A3-OH)。研究包括电子自旋共振(ESR)测量和 DFT 动力学研究。在生理条件下,利用基于量子力学的整体自由基清除活性测试(QM-ORSA)评估了抗自由基机制的热力学和动力学参数--法式氢原子转移(f-HAT)、自由基加合物形成(RAF)、电子转移后的顺序质子丢失(SPLET)和质子转移后的单电子转移(SET-PT)。ESR 结果表明,抗自由基活性的下降顺序为 A1-OH (58.7%) > A2-OH (57.5%) > A3-OH (53.1%)。动力学分析表明,f-HAT 机制主导了 HOO- 失活。一种新提出的 "质子顺序损失与自由基加成(SPL-RAF)"机制描述了与 O2-的相互作用。对 O2--的活性为 A2-OH (1.26 × 106 M-1s-1) > A3-OH (7.71 × 105 M-1s-1) > A1-OH(4.22 × 105 M-1s-1)。分子对接和动力学研究测试了对产生活性物种的酶的抑制能力:脂氧合脢 (LOX)、髓过氧化物酶 (MPO)、NAD(P)H 氧化酶 (NOX) 和黄嘌呤氧化酶 (XOD)。与酶的亲和力依次降低:XOD > LOX > NOX > MPO。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The inhibitory potential of 4,7-dihydroxycoumarin derivatives on ROS-producing enzymes and direct HOO•/o2• - radical scavenging activity - a comprehensive kinetic DFT study.
This study examined the antiradical activity of three synthesized coumarin derivatives: (E)-3-(1-((2-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A1-OH), (E)-3-(1-((3-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A2-OH), and (E)-3-(1-((4-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A3-OH) against HOO•/O2•- radical species. The investigation included electron spin resonance (ESR) measurements and a DFT kinetic study. Thermodynamic and kinetic parameters of antiradical mechanisms-Formal Hydrogen Atom Transfer (f-HAT), Radical Adduct Formation (RAF), Sequential Proton Loss followed by Electron Transfer (SPLET), and Single-Electron Transfer followed by Proton Transfer (SET-PT)-were evaluated using the Quantum Mechanics-based test for Overall Free Radical Scavenging Activity (QM-ORSA) under physiological conditions. ESR results indicated antiradical activity decreased in the sequence A1-OH (58.7%) > A2-OH (57.5%) > A3-OH (53.1%). Kinetic analysis revealed the f-HAT mechanism dominated HOO• inactivation. A newly formulated Sequential Proton Loss followed by Radical Adduct Formation (SPL-RAF) mechanism described interactions with O2•-. The activity toward O2•- was A2-OH (1.26 × 106 M-1s-1) > A3-OH (7.71 × 105 M-1s-1) > A1-OH (4.22 × 105 M-1s-1). Molecular docking and dynamics studies tested inhibitory capability against enzymes producing reactive species: Lipoxygenase (LOX), Myeloperoxidase (MPO), NAD(P)H oxidase (NOX), and Xanthine Oxidase (XOD). Affinity to enzymes decreased in the order: XOD > LOX > NOX > MPO.
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来源期刊
Free Radical Research
Free Radical Research 生物-生化与分子生物学
CiteScore
6.70
自引率
0.00%
发文量
47
审稿时长
3 months
期刊介绍: Free Radical Research publishes high-quality research papers, hypotheses and reviews in free radicals and other reactive species in biological, clinical, environmental and other systems; redox signalling; antioxidants, including diet-derived antioxidants and other relevant aspects of human nutrition; and oxidative damage, mechanisms and measurement.
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