Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell
- Eur J Med Chem. 2023 Feb 15:248:115092. doi: 10.1016/j.ejmech.2023.115092.
- 1. College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, 310014, China.
- 2. General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
- 3. Department of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
- 4. Department of Chemistry, Yale University, New Haven, CT, 06520, United States; Institute of Biomolecular Design &Discovery, Yale University, West Haven, CT, 06516, United States.
- 5. College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: [email protected].
The co-administration of Anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in Anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 μM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 μM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.