College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
Department of Pharmacy, Quanzhou Medical College, Quanzhou, 362100, China.
Eur J Med Chem. 2021 Apr 15;216:113336. doi: 10.1016/j.ejmech.2021.113336. Epub 2021 Mar 2.
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC (doxorubicin) = 0.73 μM, RF = 69.6 with 5 μM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.
P-糖蛋白（P-gp）介导的多药耐药（MDR）是一种细胞对结构和机制上无关的药物产生耐药性的现象，导致细胞内药物浓度降低。这是恶性肿瘤临床治疗中的一个显著问题。因此，P-gp 蛋白是解决 MDR 的理想靶点之一。基于我们之前工作中获得的先导化合物 5m，本文设计并合成了一系列带有烷基取代苯酚和 6,7-二甲氧基-1,2,3,4-四氢异喹啉的呋喃衍生物，作为逆转 P-gp 介导的 MDR 的试剂。含有异丙氧基的化合物 16 对 MCF-7/ADR 中 P-gp 介导的 MDR 具有良好的活性（IC（阿霉素）= 0.73 μM，RF = 69.6，用 5 μM 16 处理）。Western blot 结果和 Rh123 积累实验表明，16 有效地抑制了 P-gp 的外排功能，但不影响其表达。初步的构效关系和对接研究表明，化合物 16 可能是一种潜在的 P-gp 抑制剂。最值得一提的是，化合物 16 与多种抗肿瘤药物（如阿霉素、紫杉醇和长春新碱）联合使用取得了令人满意的效果。这项研究为克服多药耐药的恶性肿瘤细胞提供了一种有希望的 P-gp 抑制剂，为进一步的研究奠定了基础。
