Laboratory of Pharmaceutical Analysis, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Rd. Zuchongzhi, Zhangjiang Hi-Tech Park, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Rd. Zuchongzhi, Zhangjiang Hi-Tech Park, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
J Pharm Biomed Anal. 2022 Nov 30;221:115056. doi: 10.1016/j.jpba.2022.115056. Epub 2022 Sep 16.
In this study a kinetic and thermodynamic atropisomeric transformation due to a hindered rotation around the tetrahydroisoquinoline-based amide group was investigated. Quantum chemistry calculations were applied to investigate the transformation under the gas phase and several solvents with different polarity, and then evaluated by dynamic HPLC determination. It was found that the transformation rate of constants and the half-life time varied under the influence of solvent polarity and temperature and the energies of rotational barrier were determined ranging between 87 and 92 kJ∙mol. A primary binding study with HSA confirmed a rapid interconversion under the simulated physiological conditions. It is therefore suggested to take this atropisomeric compound as a racemic mixture for its future drug development.
在这项研究中，研究了由于四氢异喹啉基酰胺基团的受阻旋转而导致的动力学和热力学变旋异构转化。应用量子化学计算研究了在气相和几种不同极性溶剂中的转化，并通过动态 HPLC 测定进行了评估。结果发现，溶剂极性和温度的影响下，转化速率常数和半衰期时间发生了变化，并且确定了旋转势垒的能量在 87 到 92kJ·mol 之间。与 HSA 的初步结合研究证实，在模拟生理条件下，快速互变。因此，建议将这种变旋化合物作为外消旋混合物用于其未来的药物开发。
