College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
Department of Chemistry, Yale University, New Haven, CT, 06520, USA; Institute of Biomolecular Design &Discovery, Yale University, West Haven, CT, 06516, USA.
Eur J Med Chem. 2023 Sep 5;257:115462. doi: 10.1016/j.ejmech.2023.115462. Epub 2023 May 12.
P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8. Ⅲ-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that Ⅲ-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of Ⅲ-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. Ⅲ-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model.
P-糖蛋白（P-gp）是触发细胞多药耐药（MDR）的药物外排转运蛋白之一。在此，通过对先导化合物 5m 进行主动骨架拼接和结构优化策略的利用，共设计、合成并筛选了 50 种新型 2,5-取代呋喃衍生物，用于 P-gp 抑制活性。构效关系分析确定了一个重要的药效团 N- 苯基苯甲酰胺，从而发现了有前途的药物先导化合物 Ⅲ-8。Ⅲ-8 在 MCF-7/ADR 细胞中具有广谱逆转活性和低毒性。Western blot 和 Rh123 积累测定表明，Ⅲ-8 通过抑制 P-gp 外排表现出逆转活性。分子对接分析表明，Ⅲ-8 通过与残基 Asn 721 和 Met 986 形成氢键相互作用，对 P-gp 具有很强的亲和力。Ⅲ-8 在 MCF-7/ADR 异种移植小鼠模型中被确定为一种高效且安全的 P-gp 抑制剂。
