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)![]() | |
刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2018 | |
卷号 | 146期号:2页码:157-170 |
关键词 | Euphorbia Sororia Jatrophane Diterpenoids Multidrug Resistance Reversers P-glycoprotein Modulators Structure-activity Relationship Mechanisms |
ISSN号 | 0223-5234 |
DOI | 10.1016/j.ejmech.2018.01.027 |
英文摘要 | 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. |
WOS记录号 | WOS:000427310700013 |
内容类型 | 期刊论文 |
源URL | [http://ir.xjipc.cas.cn/handle/365002/5289] ![]() |
专题 | 新疆理化技术研究所_省部共建新疆特有药用资源利用重点实验室 新疆理化技术研究所_资源化学研究室 |
通讯作者 | Aisa, HA (Aisa, Haji Akber) |
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 |
推荐引用方式 GB/T 7714 | 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 .(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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