将S-Se氧化添加到奥拉诺芬衍生物中:一项DFT研究
Hélio F Dos Santos1, Diego F S Paschoal2
1NEQC: Núcleo de Estudos em Química Computacional, Departamento de Química - ICE, Universidade Federal de Juiz de Fora, Campus Universitário, 36.036-900, Juiz de Fora, MG, Brazil. helio.santos@ufjf.br.
Physical chemistry chemical physics : PCCP
|January 29, 2024
概括
修改auranofin (AF) 金复合体上的配体显著降低了与 thioredoxin减少酶 (TrxR) 反应的能量屏障. 这项研究探讨了连接体变化如何影响AF.
科学领域:
- 无机化学 无机化学
- 药用化学 医学化学
- 计算化学计算化学
背景情况:
- 奥拉诺芬 (AF) 和它的类似物是具有已被证明的抗癌性质的黄金 (I) 复合物.
- 这些化合物通过抑制硫素减少酶 (TrxR) 酶来发挥它们的治疗作用.
- 氧化添加到Au(I) 的S-Se键通常是一种缓慢的反应,具有很高的激活屏障.
研究的目的:
- 为了研究将S-Se键氧化添加到26种奥拉诺芬衍生物的系列中.
- 探索AF连体的修改如何影响反应的激活障碍和可行性.
- 阐明控制反应机制的电子和固态因素及其与生物活动的相关性.
主要方法:
- 对26种奥拉诺芬衍生物的氧化添加反应进行计算分析.
- 激活障碍 (ΔH‡) 和反应能量 (ΔH°) 的计算.
- 在过渡状态下分析电荷转移过程和应变能量.
主要成果:
- 奥拉诺芬与S-Se键的反应具有很高的激活屏障 (33.0 kcal mol-1).
- 配体修饰,例如用-P(Et2) ((OEt) 取代-PEt3,显著降低了激活屏障,达到17.1 kcal mol-1.1.
- 用 -Cl− 替换 -SAtg 配体,导致激活屏障为 22.5 kcal mol−1.1.
- 反应主要是由S-Se键通过电荷转移对Au(I) 中心的核友性攻击驱动的.
- 过渡状态几何中的应变能量在激活屏障趋势中也起着至关重要的作用.
- 激活屏障和反应能量之间的相关性表明一种类似产品的过渡状态.
结论:
- 微妙的连接物修饰可以使氧化添加反应在温和条件下可行.
- 了解这些反应动态,可以了解AF衍生物与TrxR.的相互作用.
- 这项研究可能为开发具有更高效率的基于AF的新型抗癌药物铺平道路.
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