2. Academic Validation
  3. Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance

Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance

  • Eur J Med Chem. 2019 Oct 1:179:849-862. doi: 10.1016/j.ejmech.2019.06.066.
Chao-Yun Cai 1,  Hong Zhai 2,  Zi-Ning Lei 3,  Cai-Ping Tan 2,  Bao-Li Chen 2,  Zhao-Yi Du 2,  Jing-Quan Wang 3,  Yun-Kai Zhang 3,  Yi-Jun Wang 3,  Pranav Gupta 3,  Bo Wang 4,  Zhe-Sheng Chen 5
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, 135 Xingang West Road, Guangzhou, 510275, PR China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States.
  • 2 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, 135 Xingang West Road, Guangzhou, 510275, PR China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States.
  • 4 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, 135 Xingang West Road, Guangzhou, 510275, PR China. Electronic address: ceswb@mail.sysu.edu.cn.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, 11439, United States. Electronic address: chenz@stjohns.edu.
PMID: 31302589 DOI: 10.1016/j.ejmech.2019.06.066
Abstract

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in Cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of Anticancer drugs.

Keywords

ABCG2 transporter; Benzoyl indoles; Metabolic stability; Multidrug resistance; Reversal agents.

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