Feng Senling, Zhou Huifang, Wu Deyan, Zheng Dechong, Qu Biao, Liu Ruiming, Zhang Chen, Li Zhe, Xie Ying, Luo Hai-Bin
School of Pharmacy, State Key Laboratory for Quality Research in Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Acta Pharm Sin B. 2020 Feb;10(2):327-343. doi: 10.1016/j.apsb.2019.07.007. Epub 2019 Jul 31.
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 . 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 exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 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 P-gp inhibition. Moreover, Western blot experiments revealed that inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying of multiple mechanisms to reverse MDR in lung cancer.
我们最近的研究表明，天然产物橙皮素（NOB）是一种很有前景的多药耐药（MDR）逆转剂，可提高癌症化疗的疗效。然而，其低水溶性和全合成困难限制了它作为治疗剂的应用。为应对这些挑战，通过一条六步的简洁路线高产率地合成了NOB，并合成了14种具有显著溶解性和功效的衍生物。所有化合物在过表达P-糖蛋白（P-gp）的MDR癌细胞中对紫杉醇（PTX）的敏感性均有所提高。其中，化合物的水溶性比NOB高280倍。一种耐药A549/T异种移植模型表明，在与PTX（15 mg/kg）联合给药剂量为50 mg/kg时，比NOB更有效地抑制肿瘤生长，并通过抑制P-gp显著提高肿瘤中的PTX浓度。此外，蛋白质免疫印迹实验表明，抑制了MDR癌细胞中NRF2、磷酸化ERK和AKT的表达，从而暗示其具有逆转肺癌MDR的多种机制。
