NSC23925的新型喹啉化合物衍生物作为对抗P糖蛋白介导的多药耐药性的有效逆转剂。,Frontiers in Chemistry

当前位置： X-MOL 学术 › Front. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

NSC23925的新型喹啉化合物衍生物作为对抗P糖蛋白介导的多药耐药性的有效逆转剂。
Frontiers in Chemistry ( IF 3.8 ) Pub Date : 2019-12-19 , DOI: 10.3389/fchem.2019.00820
Xingping Quan ₁ , Hongzhi Du ₂ , Jingjing Xu ₃ , Xiaoying Hou ₁ , Xiaofeng Gong ₁ , Yao Wu ₁ , Yuqi Zhou ₁ , Jingwei Jiang ₁ , Ligong Lu ₄ , Shengtao Yuan ₁ , Xiangyu Yang ₄ , Lei Shi ₃ , Li Sun ₁

Affiliation

多药耐药性是一个严重的问题，也是导致癌症治疗失败并导致患者死亡的常见原因。尽管在临床前或临床试验中已评估了多种逆转耐药抑制剂，但尚未确定有效且低毒的逆转剂。在这项研究中，设计了一系列来自NSC23925的新型喹啉化合物衍生物来抑制P-糖蛋白（P-gp）。其中，YS-7a与维拉帕米（作为阳性对照）相比于维拉帕米，以最小的细胞毒性浓度共同孵育时，对P-gp的抑制作用更强。YS-7a在不影响P-gp表达的情况下抑制了P-gp的转运功能，但以剂量依赖的方式刺激了P-gp的ATP酶活性。接下来，分子对接用于预测六个最可能的结合位点，即SER270，VAL273，VAL274，ILE354，VAL357和PHE390。此外，YS-7a对细胞色素P450 3A4活性没有影响，对正常细胞几乎没有毒性。另外，YS-7a与长春新碱的联合治疗在体内显示出比阳性对照维拉帕米更好的抑制作用，而对小鼠体重没有负面影响。总体而言，我们的结果表明YS-7a可以通过抑制体内外P-gp转运功能来逆转癌症的多药耐药性，这表明YS-7a可能是一种新型治疗剂。YS-7a与长春新碱的联合治疗在体内显示出比阳性对照维拉帕米更好的抑制作用，而对小鼠体重没有负面影响。总体而言，我们的结果表明YS-7a可以通过抑制体内外P-gp转运功能来逆转癌症的多药耐药性，这表明YS-7a可能是一种新型治疗剂。YS-7a与长春新碱的联合治疗在体内显示出比阳性对照维拉帕米更好的抑制作用，而对小鼠体重没有负面影响。总体而言，我们的结果表明YS-7a可以通过抑制体内外P-gp转运功能来逆转癌症的多药耐药性，这表明YS-7a可能是一种新型治疗剂。

"点击查看英文标题和摘要"

Novel Quinoline Compound Derivatives of NSC23925 as Potent Reversal Agents Against P-Glycoprotein-Mediated Multidrug Resistance.

Multidrug resistance is a serious problem and a common cause of cancer treatment failure, leading to patient death. Although numerous reversal resistance inhibitors have been evaluated in preclinical or clinical trials, efficient and low-toxicity reversal agents have not been identified. In this study, a series of novel quinoline compound derivatives from NSC23925 were designed to inhibit P-glycoprotein (P-gp). Among them, YS-7a showed a stronger inhibitory effect against P-gp than verapamil, as a positive control, when co-incubated with chemotherapy drugs at minimally cytotoxic concentrations. YS-7a suppressed the P-gp transport function without affecting the expression of P-gp but stimulated the ATPase activity of P-gp in a dose-dependent manner. Next, molecular docking was used to predict the six most probable binding sites, namely, SER270, VAL273, VAL274, ILE354, VAL357, and PHE390. Moreover, YS-7a had no effect on cytochrome P450 3A4 activity and showed little toxicity to normal cells. In addition, combined treatment of YS-7a with vincristine showed a better inhibitory effect than the positive control verapamil in vivo without a negative effect on mouse weight. Overall, our results showed that YS-7a could reverse cancer multidrug resistance through the inhibition of P-gp transport function in vitro and in vivo, suggesting that YS-7a may be a novel therapeutic agent.

更新日期：2019-12-19

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南