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

• 来源期刊: 药学学报（英文版）
• 关键词: Nobiletin Cancer multidrug resistance Mechanism Nobiletin P-gp inhibition Reversal agents Solubility Total synthesis
• 年，卷（期）: 2020,（2）
• 页码范围: 327-343
• 页数: 17页
• 语种: 英文

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 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.