Original articles
Senling Feng, Huifang Zhou, Deyan Wu, Dechong Zheng, Biao Qu, Ruiming Liu, Chen Zhang, Zhe Li, Ying Xie, Hai-Bin Luo. Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 327-343

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents
Senling Fenga, Huifang Zhoub, Deyan Wub, Dechong Zhenga, Biao Qua, Ruiming Liua, Chen Zhangb, Zhe Lib, Ying Xiea, Hai-Bin Luob
a School of Pharmacy, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China;
b School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.
Key words:    Nobiletin    Cancer multidrug resistance    Mechanism    Nobiletin    P-gp inhibition    Reversal agents    Solubility   
Received: 2019-04-07     Revised: 2019-07-05
DOI: 10.1016/j.apsb.2019.07.007
Funds: This work was supported by National Key R&D Program of China (2017YFB0202600), Macao Science and Technology Development Fund, Macau Special Administrative Region (003/2017/A1 to Ying Xie, China), National Natural Science Foundation of China (21572279, 21877134, 81602955 and 81703341), Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016, China).
Corresponding author: Ying Xie, Hai-Bin Luo     Email:yxie@must.edu.mo;luohb77@mail.sysu.edu.cn
Author description:
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Senling Feng
Huifang Zhou
Deyan Wu
Dechong Zheng
Biao Qu
Ruiming Liu
Chen Zhang
Zhe Li
Ying Xie
Hai-Bin Luo

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