PDF(Pubmed)
Abstract：
Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds.
摘要：
非酶催化的硫醇加成到α上，β-不饱和羰基体系与多种生物学效应有关。在不同的pH值（pH3.2、7.4和8.0）下，研究了还原型谷胱甘肽（GSH）和N-乙酰半胱氨酸（NAC）向六元环状查尔酮类似物2a和2b的非酶催化亲核加成的动力学和非对映选择性。所选化合物显示不同数量级的体外癌细胞细胞毒性(IC50)。查耳酮在所有孵育条件下都与两种硫醇本质上反应。最终混合物的初始速率和组成取决于取代和pH。使用具有UV检测的高压液相色谱(HPLC-UV)评估反应的立体化学结果。通过高压液相色谱-质谱(HPLC-MS)确认形成的硫醇-缀合物和逆-迈克尔产物(Z)-2a和(Z)-2b的结构。进行了前沿分子轨道和福井函数计算，以研究它们对六元环状类似物的影响。将数据与用开链(1)和七元(3)类似物获得的数据进行比较。观察到的反应性与化合物的体外癌细胞细胞毒性的差异不直接相关。
