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  3. Rational discovery of novel tetrahydroisoquinoline-indole derivatives as potent P-glycoprotein inhibitor against multidrug resistance in MCF-7/ADR cell

Rational discovery of novel tetrahydroisoquinoline-indole derivatives as potent P-glycoprotein inhibitor against multidrug resistance in MCF-7/ADR cell

  • Bioorg Chem. 2025 Sep:164:108854. doi: 10.1016/j.bioorg.2025.108854.
Zhikun Yang 1,  Leyi Ying 2,  Ning Yang 3,  Xue Yang 4,  Hui Yan 3,  Jiajia Han 2,  Yanhong Yang 2,  Xiaozhou Mou 5,  Hong Wang 6,  Yasheng Li 7
Affiliations

Affiliations

  • 1 Department of Infectious Diseases & Anhui Province Key Laboratory of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou 310014, China.
  • 2 College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou 310014, China.
  • 3 Department of Infectious Diseases & Anhui Province Key Laboratory of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 4 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; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
  • 5 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.
  • 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.
  • 7 Department of Infectious Diseases & Anhui Province Key Laboratory of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China. Electronic address: liyasheng@ahmu.edu.cn.
PMID: 40811900 DOI: 10.1016/j.bioorg.2025.108854
Abstract

A key strategy for overcoming multidrug resistance (MDR) involves developing inhibitors for the chemotherapy drug efflux pump, P-glycoprotein (P-gp). In this study, building on the prior exploration of the tetrahydroisoquinoline-indole scaffold and receptor-based drug design, the amino group on the indole underwent nucleophilic substitution, leading to 20 novel tetrahydroisoquinoline-benzyl-1H-indole derivatives. The exploration of structure-activity relationships (SAR) revealed that compound BP3p exhibited low cytotoxicity and potent MDR reversal activity against doxorubicin in MCF7/ADR cells (IC50 = 0.11 μM, reversal fold = 215.9), surpassing the reported P-gp inhibitor cyclosporine A. Furthermore, mechanistic studies indicate that BP3p's MDR reversal activity stems from inhibiting the efflux function of P-gp but not expression, and BP3p could bind to P-gp directly and induced a conformation change of P-gp. Moreover, molecular docking simulations further confirm that BP3p shows a strong affinity for P-gp, while 3D tumor spheroid models suggest that BP3p exhibits significant reversal activity against doxorubicin-resistant cells, underscoring its potential to overcome tumor resistance in vivo. These findings position BP3p as a promising P-gp inhibitor, offering valuable insights for the future development of novel P-gp inhibitors.

Keywords

MCF-7/ADR; Molecular docking; P-glycoprotein; Structure-activity relationship; Tetrahydroisoquinoline-indole derivatives.

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