State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, People's Republic of China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, People's Republic of China.
J Nat Prod. 2020 Dec 24;83(12):3536-3544. doi: 10.1021/acs.jnatprod.0c00364. Epub 2020 Dec 3.
In the ongoing efforts to discover natural cholesterol-lowering compounds, dihydrocucurbitacin B, isolated from roots, was found to promote LDL uptake by upregulating LDLR protein in a PCSK9-dependent process. In this study, an in-depth investigation of roots afforded 27 cucurbitacins (-), including seven new cucurbitacins (-), and their structures were elucidated by spectroscopic data analyses. In order to gain insight into their structure-activity relationship, cucurbitacin derivatives (- and -) were synthesized. Evaluation of lipid-lowering activities of these cucurbitacins by an LDL uptake assay in HepG2 cells revealed that most of the compounds improved the LDL uptake rate, among which hexanorisocucurbitacin D () and isocucurbitacin D () exhibited the highest activities (rates of 2.53 and 2.47, respectively), which were comparable to that of the positive control, nagilactone B (rate of 2.07). According to a mechanistic study by Western blot analysis, compounds and dose-dependently increased LDLR protein levels and reduced PCSK9 protein levels, representing promising new lipid-lowering drug candidates.
在寻找天然降胆固醇化合物的持续努力中，从苦瓜属植物的根部分离得到的二氢苦瓜素 B 被发现通过依赖于 PCSK9 的过程上调 LDLR 蛋白来促进 LDL 的摄取。在这项研究中，对苦瓜属植物的根进行了深入研究，得到了 27 种苦瓜素（-），包括 7 种新的苦瓜素（-），并通过光谱数据分析阐明了它们的结构。为了深入了解它们的结构-活性关系，合成了苦瓜素衍生物（-和-）。通过 HepG2 细胞中的 LDL 摄取测定评估这些苦瓜素的降脂活性，发现大多数化合物都提高了 LDL 的摄取率，其中六氢鹅绒藤次碱 D（）和异苦瓜素 D（）表现出最高的活性（分别为 2.53 和 2.47），与阳性对照纳吉利酮 B（速率为 2.07）相当。根据 Western blot 分析的机制研究，化合物和剂量依赖性地增加了 LDLR 蛋白水平并降低了 PCSK9 蛋白水平，这代表了有前途的新型降脂药物候选物。
