Robustadial A and B from Eucalyptus globulus Labill. and their anticancer activity as selective tyrosyl-DNA phosphodiesterase 2 inhibitors

被引:8
|
作者
Zhang, Yu [1 ]
He, Xiao-Zhi [2 ]
Yang, Hao [1 ]
Liu, Hai-Yang [2 ]
An, Lin-Kun [1 ,3 ]
机构
[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China
[2] Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming Inst Bot, Kunming, Yunnan, Peoples R China
[3] Guangdong Prov Key Lab New Drug Design & Evaluat, Guangzhou, Peoples R China
关键词
anticancer; Eucalyptus globulus Labill; inhibitors; synergistic effect; tyrosyl-DNA phosphodiesterase; SMALL-MOLECULE INHIBITORS; 1; TDP1;
D O I
10.1002/ptr.7207
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered DNA repair enzyme that can repair topoisomerase 2-mediated DNA damage, resulting in cancer cell resistance. In this study, two compounds, robustadial A and B, were isolated from a fraction of the ethyl acetate extract of Eucalyptus globulus Labill. fruits based on TDP2 inhibition screening. The biological experiments indicated that robustadial A and B have TDP2 inhibitory activity with EC50 values of 17 and 42 mu M, respectively, but no tyrosyl-DNA phosphodiesterase 1 inhibition at 100 mu M. Robustadial A showed significant synergistic effects with the anticancer drug etoposide in four human cancer cell lines, non-small cell lung cancer cell line (A549), prostate cancer cell line (DU145), breast cancer cell line (MCF-7), colorectal adenocarcinoma cell line (HCT-116), and chicken lymphoma cell line (DT40), and chicken lymphoma cell line complementation with human TDP2 (DT40 hTDP2) with combination index values ranging from 0.21 to 0.74. This work will facilitate future efforts for the development of robustadial A-based TDP2 selective inhibitors.
引用
收藏
页码:5282 / 5289
页数:8
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