Department of Applied Biology and Chemical Technology, State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong SAR, China.
J Med Chem. 2012 Mar 8;55(5):1999-2014. doi: 10.1021/jm201121b. Epub 2012 Feb 22.
Here we report a great improvement in reversal potency of cancer drug resistance when flavonoid dimers possess a functionally substituted aminopolyethylene glycol linker. The most potent compound, 18, contains a N-benzyl group at the linker. It has many advantages including (1) high potencies in reversing P-glycoprotein (P-gp) mediated resistance in LCC6MDR cells to various anticancer drugs with EC(50) in the nanomolar range, (2) low toxicity and high therapeutic index, and (3) preferential inhibition of P-gp over multidrug resistance protein 1 and breast cancer resistance protein. Compound 18 stimulates P-gp-ATPase activity by 2.7-fold and mediates a dose-dependent inhibition of doxorubicin (DOX) transport activity. Lineweaver-Burk and Dixon plots suggest that 18 is a competitive inhibitor to DOX in binding to P-gp with a K(i) of 0.28-0.34 μM and a Hill coefficient of 1.17. Moreover, the LCC6MDR cell displays about 2.1-fold lower intracellular accumulation of 18 compared to the wild type, suggesting that 18 is a P-gp substrate as well.
在这里，我们报告了当黄酮二聚体具有功能取代的聚亚乙基亚胺二醇接头时，癌症药物耐药性逆转效力的显著提高。最有效的化合物 18 在接头处含有苄基。它具有许多优点，包括（1）对 LCC6MDR 细胞中各种抗癌药物的 P 糖蛋白（P-gp）介导的耐药性具有高逆转效力，EC（50）在纳摩尔范围内，（2）低毒性和高治疗指数，以及（3）优先抑制 P-糖蛋白，而不是多药耐药蛋白 1 和乳腺癌耐药蛋白。化合物 18 通过 2.7 倍刺激 P-gp-ATP 酶活性，并介导阿霉素（DOX）转运活性的剂量依赖性抑制。Lineweaver-Burk 和 Dixon 图表明，18 是与 P-gp 结合的 DOX 的竞争性抑制剂，其 K（i）为 0.28-0.34 μM，Hill 系数为 1.17。此外，LCC6MDR 细胞显示出比野生型低约 2.1 倍的 18 细胞内积累，表明 18 也是 P-糖蛋白的底物。
