Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Eur J Med Chem. 2023 Mar 15;250:115218. doi: 10.1016/j.ejmech.2023.115218. Epub 2023 Feb 21.
P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 μM IC values of hERG potassium channel inhibition concentration suggested that compound 27f hardly had relevant cardiac toxicity. These results indicated that compound 27f might be a potential candidate to further investigate for the development of chemosensitizer with MDR reversal activity.
P-糖蛋白转运体（P-gp，ABCB1）是多药耐药的主要贡献者，因此成为开发新型 P-gp 抑制剂以克服多药耐药的有价值的靶点。在这项研究中，合成了 49 种新型的 DSP 衍生物和 sec-DMDCK 衍生物，并评估了它们在 A2780/T 细胞系中对紫杉醇的化疗增敏能力。它们中的大多数表现出与维拉帕米相当的逆转多药耐药活性。特别是，化合物 27f 显示出显著的化疗增敏作用，在 A2780/T 细胞中的逆转倍数超过 425 倍。初步药理机制研究表明，化合物 27f 通过抑制 P-gp 逆转多药耐药，比维拉帕米更有效地增加紫杉醇和罗丹明 123 的积累。此外，hERG 钾通道抑制浓度的 IC 值高于 40 μM，表明化合物 27f 几乎没有相关的心脏毒性。这些结果表明，化合物 27f 可能是一个有潜力的候选药物，可进一步研究开发具有 MDR 逆转活性的化疗增敏剂。
