Nobiletin and its derivatives overcome multidrug resistance(MDR) in cancer:total synthesis and discovery of potent MDR reversal agents  

作　　者：Senling Feng Huifang Zhou Deyan Wu Dechong Zheng Biao Qu Ruiming Liu Chen Zhang Zhe Li Ying Xie Hai-Bin Luo 

机构地区：[1]School of Pharmacy,State Key Laboratory for Quality Research in Chinese Medicines,Macao University of Science and Technology,Avenida Wai Long,Taipa,Macao,China [2]School of Pharmaceutical Sciences,Sun Yat-Sen University,Guangzhou 510006,China

出　　处：《Acta Pharmaceutica Sinica B》2020年第2期327-343,共17页药学学报（英文版）

基　　金：supported by National Key R&D Program of China(2017YFB0202600);Macao Science and Technology Development Fund,Macao Special Administrative Region(003/2017/A1to 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).

摘　　要：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 29 d exhibited water solubility 280-fold higher than NOB.A drug-resistance A549/T xenograft model showed that 29 d,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 29 d inhibited expression of NRF2,phosphorylated ERK and AKT in MDR cancer cells,thus implying 29 d of multiple mechanisms to reverse MDR in lung cancer.

关 键 词：NOBILETIN CANCER MULTIDRUG resistance Mechanism P-gp inhibition Reversal agents Solubility Total synthesis 

分 类 号：R914[医药卫生—药物化学] TQ464[医药卫生—药学]