化学
P-糖蛋白
多重耐药
流出
药理学
细胞毒性
粉防己碱
体内
化疗
抗药性
长春新碱
流式细胞术
阿霉素
IC50型
体外
生物化学
医学
免疫学
环磷酰胺
生物
内科学
生物技术
微生物学
抗生素
作者
Rong Zeng,Xiu-Ming Yang,Hongwei Li,Xue Li,Gui Yu,Tao Yu,Ping Yan,Wen Yuan,Shengli Niu,Jie Gu,Ying‐Chun Chen,Qin Ouyang
标识
DOI:10.1021/acs.jmedchem.2c02061
摘要
Targeted inhibition of a drug efflux transporter P-glycoprotein (P-gp) is an important strategy to reverse multidrug resistance in cancer chemotherapy. In this study, a rationally structural simplification to natural tetrandrine was performed based on molecular dynamics simulation and fragment growth, leading to an easily prepared, novel, and simplified compound OY-101 with high reversal activity and low cytotoxicity. Its excellent synergistic anti-cancer effect with vincristine (VCR) against drug-resistant cells Eca109/VCR was confirmed by reversal activity assay, flow cytometry, plate clone formation assay, and drug synergism analysis (IC50 = 9.9 nM, RF = 690). Further mechanism study confirmed that the OY-101 was a specific and efficient P-gp inhibitor. Importantly, OY-101 increased VCR sensitization in vivo without obvious toxicity. Overall, our findings may provide an alternative strategy for the design of novel specific P-gp inhibitor as an anti-tumor chemotherapy sensitizer.
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