Yu Mu-Yuan, Liu Si-Na, Liu Hui, Meng Qing-Hong, Qin Xu-Jie, Liu Hai-Yang
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Bioorg Chem. 2021 Dec;117:105404. doi: 10.1016/j.bioorg.2021.105404. Epub 2021 Oct 6.
Alzheimer's disease (AD) diagnoses are greatly increasing in frequency as the global population ages, highlighting an urgent need for new anti-AD strategies. With the aim to search for human acetylcholinesterase (hAChE) inhibitors from the species of Myrtaceae family, ten acylphloroglucinol trimers (APTs), including eight new APTs, callistemontrimers A-H (1a, 1b, 2a, 2b, 3a, 3b, 4b, and 5b), and two naturally occurring ones (4a and 5a), along with one reported triketone-acylphloroglucinol-monoterpene adduct (6), were obtained and structurally characterized from the hAChE inhibitory acetone extract of Callistemon salignus seeds. The structures and their absolute configurations for new APTs were unequivocally established via the detailed interpretation of extensive spectroscopic data (HRESIMS and NMR), ECD calculations, and single crystal X-ray diffraction, whereas the absolute configurations of known APTs were determined by further chiral separation, and calculated ECD calculations. The results of hAChE inhibitory assay revealed that an enantiomeric mixture of 2a/2b, 2a, and 2b are good hAChE inhibitors with IC values of 1.22 ± 0.23, 2.28 ± 0.19, and 4.96 ± 0.39 μM, respectively. Molecular docking was used to uncover the modes of interactions for bioactive compounds with the active site of hAChE. In addition, 2 and 6 displayed moderate neurite outgrowth-promoting effects with differentiation rates of 6.16% and 6.19% at a concentration of 1.0 μM, respectively.
随着全球人口老龄化，阿尔茨海默病（AD）的诊断频率大幅上升，这凸显了对新的抗AD策略的迫切需求。为了从桃金娘科植物中寻找人类乙酰胆碱酯酶（hAChE）抑制剂，从柳叶红千层种子的hAChE抑制丙酮提取物中获得了10种酰基间苯三酚三聚体（APT），包括8种新的APT，红千层三聚体A - H（1a、1b、2a、2b、3a、3b、4b和5b），以及2种天然存在的APT（4a和5a），还有1种已报道的三酮 - 酰基间苯三酚 - 单萜加合物（6），并对其进行了结构表征。通过对大量光谱数据（高分辨电喷雾电离质谱和核磁共振）的详细解读、电子圆二色光谱（ECD）计算以及单晶X射线衍射，明确确定了新APT的结构及其绝对构型，而已知APT的绝对构型则通过进一步的手性分离和计算ECD确定。hAChE抑制试验结果表明，2a/2b的对映体混合物、2a和2b是良好的hAChE抑制剂，IC值分别为1.22±0.23、2.28±0.19和4.96±0.39μM。分子对接用于揭示生物活性化合物与hAChE活性位点的相互作用模式。此外，化合物2和6在浓度为1.0μM时显示出中等程度的促进神经突生长的作用，分化率分别为6.16%和6.19%。
