Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People's Republic of China.
Org Biomol Chem. 2018 Nov 7;16(43):8130-8143. doi: 10.1039/c8ob02067a.
Fifteen new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperforatones A-O (1-15), along with 3 structurally related analogues (16-18), were isolated from the stems and leaves of Hypericum perforatum. Their structures and absolute configurations were established by a combination of NMR spectroscopic analyses, experimental and calculated electronic circular dichroism (ECD), modified Mosher's methods, Rh2(OCOCF3)4- and [Mo2(OAc)4]-induced ECD, X-ray crystallography, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Compound 5 was found to be the first PPAP decorated by a rare 2,2,4,4,5-(pentamethyltetrahydrofuran-3-yl)methanol moiety and an oxepane ring. Furthermore, the isolates were screened for their acetylcholinesterase (AChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitory activities. Compounds 5, 10, 11, and 15 showed desirable AChE inhibitory activities (IC50 6.9-9.2 μM) and simultaneously inhibited BACE1 (at a concentration of 5 μM) with inhibition rates of 50.3%, 34.3%, 47.2%, and 34.6%, respectively. Interestingly, compound 5 showed the most balanced inhibitory activities against both AChE and BACE1 of all the tested compounds, which means that 5 could serve as the first valuable dual-targeted PPAP for the treatment of Alzheimer's disease. Preliminary molecular docking studies of 5 with BACE1 and AChE were also performed.
从贯叶连翘的茎和叶中分离得到了 15 种新的多环多聚异戊烯基酰基间苯三酚（PPAPs），分别为 hyperforatones A-O（1-15），以及 3 种结构相关的类似物（16-18）。通过 NMR 波谱分析、实验和计算的电子圆二色性（ECD）、改进的 Mosher 方法、Rh2(OCOCF3)4-和[Mo2(OAc)4]-诱导的 ECD、X 射线晶体学以及量子化学预测（QCP）的结合，确定了它们的结构和绝对构型13C NMR 化学位移。发现化合物 5 是第一个被罕见的 2,2,4,4,5-(五甲基四氢呋喃-3-基)甲醇部分和环氧丙烷环修饰的 PPAP。此外，对这些分离物进行了乙酰胆碱酯酶（AChE）和β-淀粉样前体蛋白裂解酶 1（BACE1）抑制活性的筛选。化合物 5、10、11 和 15 表现出良好的 AChE 抑制活性（IC50 6.9-9.2 μM），同时在 5 μM 浓度下抑制 BACE1 的抑制率分别为 50.3%、34.3%、47.2%和 34.6%。有趣的是，化合物 5 对 AChE 和 BACE1 的抑制活性最为平衡，这意味着 5 可能成为第一个有价值的用于治疗阿尔茨海默病的双重靶向 PPAP。还对 5 与 BACE1 和 AChE 的初步分子对接研究进行了研究。
