State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, South China Agricultural University, Guangzhou, 510642, China.
Department of Pharmacy, Quanzhou Medical College, Quanzhou, 362100, China.
Eur J Med Chem. 2018 May 10;151:546-556. doi: 10.1016/j.ejmech.2018.04.012. Epub 2018 Apr 5.
Multidrug resistance (MDR) is a tendency in which cells become resistant to structurally and mechanistically unrelated drugs, which is mediated by P-glycoprotein (P-gp). It is one of the noteworthy problems in cancer therapy. As one of the most important drugs in cancer therapy, doxorubicin has not good effectiveness if used independently. So targeting the P-gp protein is one of the key points to solve the MDR. Three series of furan derivatives containing tetrahydroquinoline or tetrahydroisoquinoline were designed and synthesized as P-gp inhibitors in this paper. Compound 5m containing 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline possessed good potency against P-gp (EC = 0.89 ± 0.11 μM). The preliminary structure-activity relationship and docking studies demonstrated that compound 5m would be great promise as a lead compound for further study. Most worthy of mention is drug combination of doxorubicin and 5m displayed antiproliferative effect of about 97.8%. This study provides highlighted P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance especially doxorubicin resistance setting the basis for further studies.
多药耐药性（MDR）是一种细胞对结构和机制上无关的药物产生耐药性的趋势，这种耐药性是由 P-糖蛋白（P-gp）介导的。它是癌症治疗中值得注意的问题之一。阿霉素作为癌症治疗中最重要的药物之一，如果单独使用，效果并不理想。因此，靶向 P-gp 蛋白是解决 MDR 的关键之一。本文设计并合成了含有四氢喹啉或四氢异喹啉的三个系列呋喃衍生物作为 P-gp 抑制剂。含有 6,7-二甲氧基-1,2,3,4-四氢异喹啉的化合物 5m 对 P-gp 具有良好的抑制活性（EC=0.89±0.11μM）。初步的构效关系和对接研究表明，化合物 5m 很有希望成为进一步研究的先导化合物。最值得一提的是，阿霉素和 5m 的药物组合显示出约 97.8%的抗增殖作用。这项研究为进一步研究提供了一种有前途的 P-gp 抑制剂，以抵抗多药耐药性，特别是阿霉素耐药性，为进一步研究奠定了基础。
