State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; University of Chinese Academy of Sciences, Beijing 100039, PR China.
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China.
Bioorg Chem. 2021 Jul;112:104989. doi: 10.1016/j.bioorg.2021.104989. Epub 2021 May 13.
Eight new jatrophane diterpenoids, Euphosorophane F-M (1-8), as well as fourteen known jatrophane diterpenoids (9-22) were separated and purified from the fructus of Euphorbia sororia, and the chemical structures were determined based on extensive spectroscopic analysis, 1D, 2D NMR and HRESIMS data included. Their absolute configurations of compounds 1, 2, 9, and 22 were elucidated by X-ray crystallographic analysis. These jatrophane diterpenoids showed lower cytotoxicity and compounds 3, 4, 11, 12, 13, 14, and 20 revealed promising multidrug resistance (MDR) reversal ability as modulators compared to verapamil (VRP) by MTT assay. The structure-activity relationship (SAR) exhibited that the absence of keto-carbonyl at C-9 and C-14 was essential to MDR reversal activity and the acyloxies substitution at C-5, C-7, C-8, and C-14 also made the activity difference. Euphosorophane I (4) particularly unfold greater potency (EC = 1.82 μM) in reversing P-gp-mediated resistance to doxorubicin (DOX). As shown by fluorescence microscopy, 4 promoted intracellular accumulation of rhodamine 123 (Rh123) and DOX in a dose-dependentmanner than VRP. Flow cytometry indicated that 4 inhibitedP-glycoprotein (P-gp) -dependentRh123 efflux in drug-resistant MCF-7/ADR cells. 4 stimulated P-gp-ATPase activity in a concentration-dependent way and inhibited DOX transport activity. Western blot and real-time qPCR results further illustrated that 4 exhibited superior MDR reversal effect in MCF-7/ADR cells attributed to the activation of ATPase rather than the upregulation of P-gp expression and mRNA levels. In addition, 4 bond to the drug-binding site of P-gp predicted by the molecular docking analysis. Collectively, these results indicated that 4 efficiently reversed P-gp-mediated MDR via inhibiting the ABCB1 drug efflux function. 4 with the advantage of low toxicity and efficient could be used as an adjuvanttherapy drug for breast cancer.
从大戟属植物Euphorbia sororia 的果实中分离得到了 8 个新的 jatrophane 二萜类化合物 Euphosorophane F-M（1-8）以及 14 个已知的 jatrophane 二萜类化合物（9-22）。通过广泛的光谱分析、1D、2D NMR 和 HRESIMS 数据确定了它们的化学结构。通过 X 射线晶体学分析确定了化合物 1、2、9 和 22 的绝对构型。这些 jatrophane 二萜类化合物的细胞毒性较低，与维拉帕米（VRP）相比，化合物 3、4、11、12、13、14 和 20 作为调节剂显示出有希望的多药耐药（MDR）逆转能力，通过 MTT 测定。构效关系（SAR）表明，C-9 和 C-14 处不存在酮羰基对于 MDR 逆转活性是必不可少的，并且 C-5、C-7、C-8 和 C-14 处的酰氧基取代也使活性产生差异。Euphosorophane I（4）特别在逆转 P-糖蛋白介导的多柔比星（DOX）耐药方面表现出更大的效力（EC=1.82μM）。荧光显微镜观察结果表明，4 以剂量依赖的方式促进罗丹明 123（Rh123）和 DOX 的细胞内积累，优于 VRP。流式细胞术表明，4 抑制了耐药 MCF-7/ADR 细胞中 P-糖蛋白（P-gp）依赖性 Rh123 外排。4 以浓度依赖的方式刺激 P-糖蛋白-ATP 酶活性并抑制 DOX 转运活性。Western blot 和实时 qPCR 结果进一步表明，4 在 MCF-7/ADR 细胞中表现出优越的 MDR 逆转作用，这归因于 ATP 酶的激活而不是 P-gp 表达和 mRNA 水平的上调。此外，4 通过分子对接分析与 P-gp 的药物结合位点结合。总之，这些结果表明，4 通过抑制 ABCB1 药物外排功能有效地逆转了 P-gp 介导的 MDR。4 具有低毒性和高效的优势，可作为乳腺癌的辅助治疗药物。
