Wu Yuxiang, Pan Miaobo, Dai Yuxuan, Liu Baomin, Cui Jian, Shi Wei, Qiu Qianqian, Huang Wenlong, Qian Hai
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Nan Jing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, NO. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu, PR China.
Bioorg Med Chem. 2016 May 15;24(10):2287-97. doi: 10.1016/j.bmc.2016.03.065. Epub 2016 Apr 1.
A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.
通过点击化学设计并合成了一系列新型的具有三唑-N-苯乙基-四氢异喹啉或三唑-N-乙基-四氢异喹啉骨架的P-糖蛋白（P-gp）介导的多药耐药（MDR）抑制剂。大多数合成化合物显示出比维拉帕米（VRP）更高的逆转活性。其中，最有效的化合物4与已知的强效P-gp抑制剂WK-X-34具有相当的活性，对K562细胞的细胞毒性较低（IC50>100μM）。与VRP相比，化合物4在增加K562/A02 MDR细胞中的药物积累方面表现出更强的效力。此外，化合物4可以以剂量依赖的方式显著逆转MDR，并且比VRP具有更长的化学增敏作用且具有可逆性。进一步的机制研究表明，化合物4可以显著增加阿霉素（ADM）在K562/A02细胞中的细胞内积累，并抑制罗丹明-123（Rh123）从细胞中流出。这些结果表明，化合物4可能是开发P-gp介导的MDR抑制剂的有前途的候选物。
