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Design, synthesis, and biological evaluation of NAD(P)H: quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation

Xu, Shengtao; Yao, Hong; Pei, Lingling; Hu, Mei; Li, Dahong; Qiu, Yangyi; Wang, Guangyu; Wu, Liang; Yao, Hequan; Zhu, Zheying; Xu, Jinyi

Authors

Shengtao Xu

Hong Yao

Lingling Pei

Mei Hu

Dahong Li

Yangyi Qiu

Guangyu Wang

Liang Wu

Hequan Yao

ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu



Abstract

The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC50 ¼ 0.263e2.904 mM), while NQO1-defficient lung adenosquamous carcinoma cells (H596) were less sensitive to these compounds, among which, compound 29h exhibited the most potent antiproliferative activity against both A549 and HT-29 cells, with IC50 values of 0.386 and 0.263 mM, respectively. Further HPLC and docking studies demonstrated that 29h is a good substrate of NQO1. Moreover, the investigation of anticancer mechanism showed that the representative compound 29h affected cell cycle and induced NQO1 dependent apoptosis through an oxidative stress triggered mitochondria-related pathway in A549 cells. Besides, the antitumor activity of 29h was also verified in a liver cancer xenograft mouse model. Biological evaluation of these compounds concludes that there is a strong correlation between NQO1 enzyme and induction of cancer cell death. Thus, this suggests that some of the target compounds activated by NQO1 are novel prodrug candidates potential for selective anticancer therapy.

Citation

Xu, S., Yao, H., Pei, L., Hu, M., Li, D., Qiu, Y., …Xu, J. (2017). Design, synthesis, and biological evaluation of NAD(P)H: quinone oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation. European Journal of Medicinal Chemistry, 132, https://doi.org/10.1016/j.ejmech.2017.03.055

Journal Article Type Article
Acceptance Date Mar 22, 2017
Online Publication Date Mar 25, 2017
Publication Date May 26, 2017
Deposit Date May 18, 2017
Publicly Available Date May 18, 2017
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 132
DOI https://doi.org/10.1016/j.ejmech.2017.03.055
Keywords NQO1, Oridonin, Indolequinone, Hypoxia-selective, Antitumor
Public URL http://eprints.nottingham.ac.uk/id/eprint/42902
Publisher URL http://www.sciencedirect.com/science/article/pii/S0223523417302143
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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