Department of Pharmaceutical Chemistry, Third Military Medical University, Chongqing 400038, China.
J Med Chem. 2023 Mar 23;66(6):4086-4105. doi: 10.1021/acs.jmedchem.2c02061. Epub 2023 Mar 9.
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 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 (IC = 9.9 nM, RF = 690). Further mechanism study confirmed that the was a specific and efficient P-gp inhibitor. Importantly, increased VCR sensitization 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.
靶向抑制药物外排转运蛋白 P-糖蛋白（P-gp）是逆转癌症化疗多药耐药的重要策略。在这项研究中，基于分子动力学模拟和片段生长，对天然的汉防己甲素进行了合理的结构简化，得到了一种易于制备、新颖且简化的化合物 ，具有高逆转活性和低细胞毒性。通过逆转活性测定、流式细胞术、平板克隆形成测定和药物协同作用分析（IC = 9.9 nM，RF = 690）证实了其与长春新碱（VCR）对耐药细胞 Eca109/VCR 的优异协同抗癌作用。进一步的机制研究证实， 是一种特异性和高效的 P-gp 抑制剂。重要的是， 增加了 VCR 的敏感性而没有明显的毒性。总的来说，我们的研究结果可能为设计新型特异性 P-gp 抑制剂作为抗肿瘤化疗增敏剂提供了一种替代策略。
