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Reactions of radicals with PERK kinase inhibitor and its analogue under oxidative and reductive stress conditions. Pulse radiolysis study
Radiation Physics and Chemistry ( IF 2.9 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.radphyschem.2020.108831
Karolina Radomska , Marian Wolszczak , Ireneusz Majsterek

Abstract The scavenging of primary free radicals generated during radiolysis of water ( e aq − , •OH, •H) and CO2•‒ (reducing radical) or N3• (oxidizing radical) by PERK inhibitor, AMD (3-acetyl-6-methylheptane-2,4-dione) and APD (3-acetyl-2,4-pentanedione) has been studied with details. AMD is a low molecular weight inhibitor of the PERK-dependent antiproliferative signaling pathway and constitutes the foundation of an innovative therapeutic strategy in the treatment of cancer diseases. The applied compounds exist in the three different forms depending on pH of aqueous solution: ketone, enol and enolate form. The effect of pH on the absorption spectra of AMD and APD has been studied and the value of pKa for the keto – enol equilibrium (conversion of the ketone to enol) and pKa for the enol – enolate form were calculated. Redox processes studied by pulse radiolysis method were more effective at neutral or alkaline pH than in an acidic solution. The influence of human serum albumin (HSA) on the oxidation and reduction process of examined compounds was studied. The kinetics of radicals reaction with tested compounds has been compared for neat buffer solution and systems containing HSA. The results indicate competitive electron scavenging by studied scavengers and protein.

中文翻译:

自由基与 PERK 激酶抑制剂及其类似物在氧化和还原应激条件下的反应。脉冲辐解研究

摘要 PERK 抑制剂 AMD (3-acetyl-6-甲基庚烷-2,4-二酮)和 APD(3-乙酰基-2,4-戊二酮)进行了详细研究。AMD 是一种 PERK 依赖性抗增殖信号通路的低分子量抑制剂,构成了治疗癌症疾病的创新治疗策略的基础。根据水溶液的pH值,应用的化合物以三种不同的形式存在:酮、烯醇和烯醇化物形式。已经研究了 pH 值对 AMD 和 APD 吸收光谱的影响,并计算了酮 - 烯醇平衡(酮转化为烯醇)的 pKa 值和烯醇 - 烯醇形式的 pKa。通过脉冲辐射分解法研究的氧化还原过程在中性或碱性 pH 值下比在酸性溶液中更有效。研究了人血清白蛋白(HSA)对受试化合物氧化和还原过程的影响。已经比较了纯缓冲溶液和含有 HSA 的系统的自由基与测试化合物反应的动力学。结果表明所研究的清除剂和蛋白质具有竞争性的电子清除作用。
更新日期:2020-07-01
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