Total Synthesis, Structure Revision, and Neuroprotective Effect of Hericenones C-H and Their Derivatives
Total Synthesis, Structure Revision, and Neuroprotective Effect of Hericenones C-H and Their Derivatives
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DOI：
10.1021/acs.joc.0c02681
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发表时间：
2021-01-25
影响因子：
3.6
通讯作者：
Nagai, Kaoru
中科院分区：
文献类型：
--
作者：
Kobayashi, Shoji;Tamura, Tomoki;Nagai, Kaoru
首次实现了hericenone C-H和“推定的3-羟基hericenone F”的全合成。合成的亮点包括直接构建间苯二酚核和香叶基侧链，通过顺序的O-香叶基化和粘土/沸石介导的O -> C重排反应组装天然产物骨架，以及仿生环化以形成多种双环天然hericenones及其同系物。通过对环化模式的深入分析和核磁共振波谱研究，将“3-羟基hericenone F”的结构修正为环氧hericenone C的5-外环化产物（命名为hericenone Z）。为了深入了解猴头菌中香叶基间苯二酚的生物学功能，系统地评价了其对内质网（ER）应激依赖性细胞死亡的潜在神经保护作用，以阐明基本的构效关系。在测定的化合物中，含有亚油酸酯的hericenone类似物，即，发现hericene D的区域异构体对衣霉素和毒胡萝卜素诱导的ER应激依赖性细胞死亡具有最有效的神经保护作用。
The first total syntheses of hericenones C-H and "putative 3-hydroxyhericenone F" were achieved. Highlights of the synthesis include the straightforward construction of the resorcinol core and geranyl side chain, assembly of the natural product skeleton by sequential O-geranylation and a clay/zeolite-mediated O -> C rearrangement reaction, and a biomimetic cyclization to form a variety of bicyclic natural hericenones and their congeners. The structure of the "putative 3-hydroxyhericenone F" was revised as the 5-exo cyclization product (named: hericenone Z) of epoxyhericenone C through in-depth analyses of the cyclization modes in addition to NMR spectroscopic studies. To gain insights into the biological functions of geranyl-resorcinols in Hericium erinaceus, potential neuroprotective effects against endoplasmic reticulum (ER) stress-dependent cell death were evaluated systematically to clarify a fundamental structure-activity relationship. Among the compounds assayed, the linoleate-containing hericenone analogue, i.e., the regioisomer of hericene D, was found to possess the most potent neuroprotective effect against tunicamycin and thapsigargin-induced ER stress-dependent cell death.