<br>WK-X-34 衍生物作为 P-糖蛋白 (P-gp/ABCB1) 抑制剂逆转多药耐药性的合成和评价,RSC Medicinal Chemistry

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WK-X-34 衍生物作为 P-糖蛋白 (P-gp/ABCB1) 抑制剂逆转多药耐药性的合成和评价
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2023-12-07 , DOI: 10.1039/d3md00612c
Fei Cao _{1,

2} , Yulong Li ₃ , Furong Ma ₃ , Zumei Wu ₃ , Zheshen Li ₄ , Zhe-Sheng Chen ₄ , Xiangdong Cheng _{1,

5} , Jiang-Jiang Qin _{1,

5} , Jinyun Dong _{1,

5}

Affiliation

恶性肿瘤中多药耐药性（MDR）的出现是许多化疗药物目前遇到的主要威胁之一。提出的克服 MDR 的策略是禁用 P-糖蛋白 (P-gp/ABCB1) 的外排功能，P-糖蛋白是 ABC 转运蛋白家族的重要成员，可显着增加各种抗癌药物从肿瘤细胞的外排。在本研究中，基于生物等排和片段生长策略对第三代P-gp抑制剂WK-X-34进行结构修饰，发现了金刚烷衍生物PID-9 ，其表现出最佳的MDR逆转活性（IC ₅₀ = 0.1338 μM，RF = 78.6）在该系列中，超过了报道的 P-gp 抑制剂维拉帕米和 WK-X-34。此外，与WK-X-34相比， PID-9对细胞的毒性降低。此外，机制研究表明金刚烷衍生物PID-5 、 PID-7和PID-9的逆转活性源于对P-gp外流的抑制。这些结果表明，化合物PID-9是其中最有效的P-gp抑制剂，具有低毒性和高MDR逆转活性，为进一步发现新型、有效、无毒的P-gp抑制剂提供了基础结构参考。

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Synthesis and evaluation of WK-X-34 derivatives as P-glycoprotein (P-gp/ABCB1) inhibitors for reversing multidrug resistance

The emergence of multidrug resistance (MDR) in malignant tumors is one of the leading threats encountered currently by many chemotherapeutic agents. A proposed strategy to overcome MDR is to disable the efflux function of P-glycoprotein (P-gp/ABCB1), a critical member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells. In this study, structural modification of a third-generation P-gp inhibitor WK-X-34 based on bioisosteric and fragment-growing strategies led to the discovery of the adamantane derivative PID-9, which exhibited the best MDR reversal activity (IC₅₀ = 0.1338 μM, RF = 78.6) in this series, exceeding those of the reported P-gp inhibitors verapamil and WK-X-34. In addition, compared with WK-X-34, PID-9 showed decreased toxicity to cells. Furthermore, the mechanism studies revealed that the reversal activity of adamantane derivatives PID-5, PID-7, and PID-9 stemmed from the inhibition of P-gp efflux. These results indicated that compound PID-9 is the most effective P-gp inhibitor among them with low toxicity and high MDR reversal activity, which provided a fundamental structural reference for further discovery of novel, effective, and non-toxic P-gp inhibitors.

更新日期：2023-12-07

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