Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance
Hu, R (Hu, Rui); Gao, J (Gao, Jie); Rozimamat, R (Rozimamat, Rushangul); Aisa, HA (Aisa, Haji Akber); Aisa, HA
2018
发表期刊EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷号146期号:2页码:157-170
摘要

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 (EC50 = 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 I was not due to the inhibiton of P-gp expression. Compound I 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 mu M. Our data suggested that I 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.

关键词Euphorbia Sororia Jatrophane Diterpenoids Multidrug Resistance Reversers P-glycoprotein Modulators Structure-activity Relationship Mechanisms
DOI10.1016/j.ejmech.2018.01.027
收录类别SCI
WOS记录号WOS:000427310700013
引用统计
被引频次:1[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/5289
专题省部共建新疆特有药用资源利用重点实验室
通讯作者Aisa, HA
作者单位1.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Zone, Urumqi 830011, Peoples R China
2.Chinese Acad Sci, State Key Lab Basis Xinjiang Indigenous Med Plant, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100039, Peoples R China
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Hu, R ,Gao, J ,Rozimamat, R ,et al. Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,146(2):157-170.
APA Hu, R ,Gao, J ,Rozimamat, R ,Aisa, HA ,&Aisa, HA.(2018).Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,146(2),157-170.
MLA Hu, R ,et al."Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 146.2(2018):157-170.
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