School of Pharmacy, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, Yancheng Teachers' University, Yancheng 224007, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Bioorg Chem. 2019 May;86:166-175. doi: 10.1016/j.bioorg.2019.01.039. Epub 2019 Jan 22.
The overexpression of P-glycoprotein plays an important role in the process of multidrug resistance (MDR). P-gp inhibitors are one of the effective strategies to reverse tumor MDR. Novel P-gp inhibitors with phthalazinone scaffolds were designed, synthesized and evaluated. Compound 26 was found to be the most promising for further study. Compound 26 possessed high potency (EC = 46.2 ± 3.5 nM) and low cytotoxicity.26 possessed high MDR reversal activity towards doxorubicin-resistant K56/A02 cells. Reversal fold (RF) value reach to 44.26. 26 also increased accumulation of doxorubicin (DOX or ADM) or other MDR-related anticancer drugs with different structures. In conclusion, compound 26 deserves more research for its good features as P-gp inhibitor.
多药耐药（MDR）过程中 P-糖蛋白的过度表达起着重要作用。P-糖蛋白抑制剂是逆转肿瘤多药耐药的有效策略之一。设计、合成并评价了具有酞嗪酮骨架的新型 P-糖蛋白抑制剂。发现化合物 26 最有希望进一步研究。化合物 26 具有高活性（EC=46.2±3.5 nM）和低细胞毒性。26 对多柔比星耐药 K56/A02 细胞具有高的多药耐药逆转活性。逆转倍数（RF）值达到 44.26。26 还增加了阿霉素（DOX 或 ADM）或其他具有不同结构的多药耐药相关抗癌药物的积累。总之，化合物 26 作为 P-糖蛋白抑制剂具有良好的特性，值得进一步研究。
