Wang Bo, Zhao Bing, Chen Zhe-Sheng, Pang Lu-Ping, Zhao Yuan-Di, Guo Qian, Zhang Xin-Hui, Liu Ying, Liu Guang-Yao, Zhang Xin-Yuan, Ma Li-Ying, Liu Hong-Min
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Eur J Med Chem. 2018 Jan 1;143:1535-1542. doi: 10.1016/j.ejmech.2017.10.041. Epub 2017 Oct 21.
ABCB1-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A series of pyrimidine-based hybrid molecules containing 1,2,3-triazole moiety were evaluated for their reversal activities against MDR. The majority of target compounds displayed moderate to great reversal potency. Among these compounds, compound 25 displayed the most potent reversal activity, about 7-fold more potent than Verapamil (VRP). Further mechanism studies revealed that compound 25 could obviously reverse paclitaxel (PTX) resistance in SW620/AD300 cells by increasing accumulation and extending maintenance of PTX. Our findings indicate that the 1,2,3-triazole-pyrimidine-based derivatives may serve as an interesting lead for the development of new potent and efficacious ABCB1-dependent MDR modulators.
ABCB1介导的多药耐药性（MDR）是癌症化疗成功的主要障碍。对一系列含有1,2,3-三唑部分的嘧啶类杂化分子进行了抗MDR逆转活性评估。大多数目标化合物表现出中等至较强的逆转效力。在这些化合物中，化合物25表现出最强的逆转活性，比维拉帕米（VRP）强约7倍。进一步的机制研究表明，化合物25可通过增加紫杉醇（PTX）的蓄积并延长其维持时间，明显逆转SW620/AD300细胞对PTX的耐药性。我们的研究结果表明，基于1,2,3-三唑-嘧啶的衍生物可能是开发新型强效且有效的ABCB1依赖性MDR调节剂的有趣先导物。
