Research Papers:

A novel synthetic derivative of quercetin, 8-trifluoromethyl-3,5,7,3′,4′-O-pentamethyl-quercetin, inhibits bladder cancer growth by targeting the AMPK/mTOR signaling pathway

Ting Tao, Caimei He, Jun Deng, Yanjun Huang, Qiongli Su, Mei Peng, Meiling Yi, Kwame Oteng Darko, Hui Zou _ and Xiaoping Yang

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Oncotarget. 2017; 8:71657-71671. https://doi.org/10.18632/oncotarget.17799

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Ting Tao1,2, Caimei He1,2, Jun Deng1,2, Yanjun Huang1,2, Qiongli Su1,2, Mei Peng1,2,4, Meiling Yi1,2, Kwame Oteng Darko1,2, Hui Zou1,2 and Xiaoping Yang1,2,3

1Key Laboratory of Small Targeted Molecules’ Discovery, Hunan Normal University, Changsha, Hunan, 410013 China

2Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, 410013 China

3Key Laboratory of Animal Nutrition and Human Health, Hunan Normal University, Changsha, Hunan, 410013 China

4Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, 410008 China

Correspondence to:

Hui Zou, email: [email protected]

Xiaoping Yang, email: [email protected]

Keywords: 8-Trifluoromethyl-3,5,7,3′,4′-O-pentamethyl-quercetin, quercetin, derivative of quercetin, AMPK, mTOR

Received: January 20, 2017     Accepted: April 27, 2017     Published: May 11, 2017


Quercetin is a naturally existing compound and shows attractive anticancer properties for a variety of solid tumors including glioma, bladder cancer, hepatocellular carcinoma, breast cancer, hematological malignancies and prostate carcinoma. However, these anticancer properties have not been clinically approved due to unclear mechanistic information and its low bioactivity. In our previous study, we elucidated that quercetin activates AMPK pathway which is the major mechanism for its unique anticancer effect in bladder cancer. In the present study, we are trying to enhance its bioactivity by chemical modification using fluorination approach to prepare novel chemical entities, based on the principle of intermediate derivative method (IDM). The compound we obtained is named 8-trifluoromethyl-3,5,7,3′,4′-O-pentamethyl- quercetin (TFQ), characterized by NMR spectra and mass spectrum (MS). The results from MTT and cologenic assay in two human and one murine bladder cancer cell lines showed that TFQ exhibits more potent inhibition on the three bladder cancer cell lines than quercetin (Que) although this enhanced effects is not very dramatic. Furthermore, we found that the survival of normal bladder cells PEBC was not significantly suppressed by TFQ compared with Que. Western blot analysis showed that TFQ possess more potent AMPK activation than Que. The downstream of AMPK was further examined by western blot. TFQ treatment is able to inactivate mTOR signaling pathway with the regulation of mTOR, 4EBP1 and P70S6K. These results demonstrated that the fluorinated quercetin derivative TFQ inhibits bladder cancer cell growth through the AMPK/mTOR pathway. Altogether, our findings suggest that TFQ could serve as a new potential therapeutic agent for bladder cancer more effective than Que.

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