Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Chem Biol Drug Des. 2018 Sep;92(3):1708-1716. doi: 10.1111/cbdd.13338. Epub 2018 Jun 14.
Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells. Compound 19 also played an important role in the P-gp efflux function of intracellular Rh123 and doxorubicin (DOX) accumulation in K562/A02 cells. Moreover, compound 19 exhibited a long lifetime of approximately 24 hr. These results indicated that compound 19 is a potential lead compound for the design of new drugs to overcome cancer MDR.
多药耐药性（MDR）仍然是化疗取得有效效果的主要障碍。需要发现新的化疗逆转剂来克服 MDR。我们的研究重点是通过点击化学获得具有 MDR 逆转能力的三唑环新型药物的更好方法。在开发的 20 种化合物中，与他利奎多尔和维拉帕米（VRP）相比，化合物 19 的细胞毒性最小，并且通过增加 K562/A02 细胞中的积累，显示出比 VRP 更高的逆转活性。化合物 19 还在 K562/A02 细胞中 Rh123 的 P-糖蛋白外排功能和阿霉素（DOX）积累的细胞内方面发挥了重要作用。此外，化合物 19 表现出约 24 小时的长半衰期。这些结果表明，化合物 19 是设计克服癌症 MDR 的新型药物的潜在先导化合物。
