Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell

Zhikun Yang; Yue Cai; Shen Mao; Qihao Wu; Mengdi Zhu; Xiaoji Cao; Bin Wei; Jin-Miao Tian; Xiaoze Bao; Xinyi Ye; Jianwei Chen; Sijia Wang; Yanlei Yu; Huawei Zhang; Xuanrong Sun; Zi-Ning Cui; Ya-Sheng Li; Hong Wang

doi:10.1016/j.ejmech.2023.115462

Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell

Eur J Med Chem. 2023 Sep 5:257:115462. doi: 10.1016/j.ejmech.2023.115462. Epub 2023 May 12.

Authors

Zhikun Yang¹, Yue Cai¹, Shen Mao¹, Qihao Wu², Mengdi Zhu³, Xiaoji Cao³, Bin Wei¹, Jin-Miao Tian¹, Xiaoze Bao¹, Xinyi Ye¹, Jianwei Chen¹, Sijia Wang¹, Yanlei Yu¹, Huawei Zhang¹, Xuanrong Sun¹, Zi-Ning Cui⁴, Ya-Sheng Li⁵, Hong Wang⁶

Affiliations

¹ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
² Department of Chemistry, Yale University, New Haven, CT, 06520, USA; Institute of Biomolecular Design &Discovery, Yale University, West Haven, CT, 06516, USA.
³ Research Center of Analysis and Measurement, Zhejiang University of Technology, Hangzhou, 310014, China.
⁴ National Key Laboratory of Green Pesticide, Integrative Microbiology Research Centre, Guangdong Province Key Laboratory of Microbial Signals and Disease Control, College of Plant Protection, South China Agricultural University, Guangzhou, 510642, China. Electronic address: ziningcui@scau.edu.cn.
⁵ Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. Electronic address: liyasheng@ahmu.edu.cn.
⁶ College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: hongw@zjut.edu.cn.

PMID: 37229830
DOI: 10.1016/j.ejmech.2023.115462

Abstract

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.

Keywords: 2,5-Disubstituted furan derivatives; MCF-7/ADR; Multidrug resistance; P-glycoprotein; Structure-activity relationship.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1*
Animals
Doxorubicin / pharmacology
Drug Resistance, Multiple*
Drug Resistance, Neoplasm
Furans / pharmacology
Glycoproteins / chemistry
Glycoproteins / metabolism
Humans
MCF-7 Cells
Mice
Molecular Docking Simulation

Substances

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Doxorubicin
Furans
Glycoproteins