Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum
Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum
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来自贯叶金丝桃的生物活性多环聚异戊二烯酰基间苯三酚
DOI：
10.1039/c8ob02067a
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发表时间：
2018
影响因子：
3.2
通讯作者：
Zhang Yonghui
中科院分区：
文献类型：
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作者：
Guo Yi;Zhang Na;Sun Weiguang;Duan Xueyan;Zhang Qing;Zhou Qun;Chen Chunmei;Zhu Hucheng;Luo Zengwei;Liu Junjun;Li Xiao-Nian;Xue Yongbo;Zhang Yonghui
从贯叶金丝桃的茎和叶中分离出15个新的多环聚异戊二烯化酰基间苯三酚（PPAP），贯叶金丝桃酮A-O（1-15），以及3个结构相关的类似物（16-18），沿着。它们的结构和绝对构型是通过NMR光谱分析、实验和计算的电子圆二色性（ECD）、改进的Mosher方法、Rh 2（OCOCF 3）4-和[Mo 2（Ac）4]-诱导的ECD、X射线晶体学以及13 C NMR化学位移的量子化学预测（QCP）的辅助来建立的。发现化合物5是第一个被稀有的2，2，4，4，5-（五甲基四氢呋喃-3-基）甲醇部分和氧杂环庚烷环修饰的PPAP。此外，筛选分离物的乙酰胆碱酯酶（AChE）和β-位点淀粉样前体蛋白裂解酶1（BACE 1）抑制活性。化合物5、10、11和15对乙酰胆碱酯酶（AChE）具有较好的抑制活性（IC 50为6.9-9.2 μM），同时对BACE 1（5 μM）具有较好的抑制作用，抑制率分别为50.3%、34.3%、47.2%和34.6%。有趣的是，化合物5在所有测试的化合物中显示出对AChE和BACE 1的最平衡的抑制活性，这意味着5可以作为第一个有价值的用于治疗阿尔茨海默病的双靶向PPAP。初步的分子对接研究5与BACE 1和乙酰胆碱酯酶。
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.