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
  • 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: [email protected].
  • 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: [email protected].
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.