School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
Key Laboratory of Tropical Plant Resources and Sustainable Use, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Menglun, Yunnan, 666303, China.
Phytochemistry. 2020 Aug;176:112395. doi: 10.1016/j.phytochem.2020.112395. Epub 2020 Apr 27.
Eight previously undescribed diterpenoids, euphoroyleans A-H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A-H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 μM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking.
从瑞香狼毒(Euphorbia royleana)全株中分离得到 8 个新的二萜类化合物，包括 2 个海松烷，3 个愈创木烷，2 个贝壳杉烷，1 个贝壳杉烯，以及 22 个已知类似物。通过广泛的光谱分析、化学转化和单晶 X 射线衍射，确定了 euphoroyleans A-H 的结构，包括绝对构型。对所有分离物进行了 P-糖蛋白(P-gp)介导的多药耐药(MDR)肝癌细胞系 HepG2/DOX 的化学反转能力筛选，其中 8 个化合物表现出显著的活性。其中，具有无明显细胞毒性的最强 MDR 调节剂活性的 ingol-3,7,12-三乙酸酯-8-苯甲酸酯，在 10 μM 时可将抗癌药物 DOX 的疗效增强约 105 倍，强于阳性药物维拉帕米。机制研究表明，ingol-3,7,12-三乙酸酯-8-苯甲酸酯可以抑制 P-gp 的转运活性，而不是其表达，通过分子对接预测了化合物与 P-gp 之间的可能识别机制。
