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; 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.
Eur J Med Chem. 2018 Feb 25;146:157-170. doi: 10.1016/j.ejmech.2018.01.027. Epub 2018 Jan 11.
Five new (1-5) and ten known (6-15) jatrophane diterpenoids were isolated from the fructus of Euphorbia sororia and their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1 and 4 were confirmed by X-ray crystallographic analysis. Cytotoxicity and anti-multidrug resistance effects of these jatrophane diterpenoids were evaluated in multidrug-resistant MCF-7/ADR breast cancer cells with an overexpression of P-glycoprotein (P-gp). Eight compounds (1, 2, 4, 6, 8, 10, 11, and 15) showed promising chemoreversal abilities compared to verapamil (VRP). The most potent compound, Euphosorophane A (1), possessed many advantages, including (1) high potency (EC = 92.68 ± 18.28 nM) in reversing P-gp-mediated resistance to doxorubicin (DOX), low cytotoxicity, and a high therapeutic index, (2) potency in reversing resistance to other cytotoxic agents associated with MDR, and (3) inhibition of P-gp-mediated Rhodamine123 (Rh123) efflux function in MCF-7/ADR cells. The results of the Western blot analysis indicated that the multidrug resistance (MDR) reversal induced by 1 was not due to the inhibiton of P-gp expression. Compound 1 stimulated P-gp-ATPase activity and caused the dose-dependent inhibition of DOX transport activity. Lineweaver-Burk and Dixon plots implied that 1 was a competitive inhibitor to DOX in the binding site of P-gp with a Ki of 0.49-0.50 μM. Our data suggested that 1 had a high binding affinity toward the DOX recognition site of P-gp. This resulted in inhibiting DOX transport, increasing intracellular DOX concentration, and finally resensitizing MCF-7/ADR to DOX. In addition, we discussed some added contents in the structure-activity relationship (SAR) of jatrophane diterpenoids.
从大戟属植物 Euphorbia sororia 的果实中分离得到了 5 个新的（1-5）和 10 个已知的（6-15）jatrophone 二萜类化合物，并通过广泛的光谱分析阐明了它们的结构。通过 X 射线晶体学分析确定了化合物 1 和 4 的绝对构型。在多药耐药 MCF-7/ADR 乳腺癌细胞中，用 P-糖蛋白（P-gp）过度表达评价了这些 jatrophane 二萜类化合物的细胞毒性和抗多药耐药性作用。与维拉帕米（VRP）相比，有 8 种化合物（1、2、4、6、8、10、11 和 15）表现出有希望的化学逆转能力。最有效的化合物 Euphosorophane A（1）具有许多优点，包括（1）在逆转 P-gp 介导的多柔比星（DOX）耐药方面具有高活性（EC=92.68±18.28 nM），低细胞毒性和高治疗指数，（2）逆转与 MDR 相关的其他细胞毒性药物的耐药性的能力，以及（3）抑制 MCF-7/ADR 细胞中 P-gp 介导的 Rhodamine123（Rh123）外排功能。Western blot 分析结果表明，1 诱导的多药耐药（MDR）逆转不是由于 P-gp 表达的抑制。化合物 1 刺激 P-gp-ATP 酶活性并导致 DOX 转运活性的剂量依赖性抑制。Lineweaver-Burk 和 Dixon 图表明，1 是 P-gp 结合部位 DOX 的竞争性抑制剂，Ki 值为 0.49-0.50 μM。我们的数据表明，1 与 P-gp 的 DOX 识别位点具有高结合亲和力。这导致抑制 DOX 转运，增加细胞内 DOX 浓度，并最终使 MCF-7/ADR 对 DOX 重新敏感。此外，我们讨论了 jatrophane 二萜类化合物结构-活性关系（SAR）中的一些附加内容。
