Biomaterial Database

Novel Quinoline Compound Derivatives of NSC23925 as Potent Reversal Agents Against P-Glycoprotein-Mediated Multidrug Resistance. 2019

Xingping Quan, and Hongzhi Du, and Jingjing Xu, and Xiaoying Hou, and Xiaofeng Gong, and Yao Wu, and Yuqi Zhou, and Jingwei Jiang, and Ligong Lu, and Shengtao Yuan, and Xiangyu Yang, and Lei Shi, and Li Sun

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.

Multidrug resistance is a serious problem and a common cause of cancer treatment failure, leading to patient death. Although numerous reversal resistance inhibitors have been evaluated in preclinical or clinical trials, efficient and low-toxicity reversal agents have not been identified. In this study, a series of novel quinoline compound derivatives from NSC23925 were designed to inhibit P-glycoprotein (P-gp). Among them, YS-7a showed a stronger inhibitory effect against P-gp than verapamil, as a positive control, when co-incubated with chemotherapy drugs at minimally cytotoxic concentrations. YS-7a suppressed the P-gp transport function without affecting the expression of P-gp but stimulated the ATPase activity of P-gp in a dose-dependent manner. Next, molecular docking was used to predict the six most probable binding sites, namely, SER270, VAL273, VAL274, ILE354, VAL357, and PHE390. Moreover, YS-7a had no effect on cytochrome P450 3A4 activity and showed little toxicity to normal cells. In addition, combined treatment of YS-7a with vincristine showed a better inhibitory effect than the positive control verapamil in vivo without a negative effect on mouse weight. Overall, our results showed that YS-7a could reverse cancer multidrug resistance through the inhibition of P-gp transport function in vitro and in vivo, suggesting that YS-7a may be a novel therapeutic agent.