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Design, synthesis, and anticancer evaluation of 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles

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Abstract

A series of 1-benzo[1,3]dioxol-5-yl-indoles bearing 3-N-fused heteroaryl moieties have been designed based on literature reports of the activity of indoles against various cancer cell lines, synthesized via a Pd-catalyzed C-N cross-coupling, and evaluated for their anticancer activity against prostate (LNCaP), pancreatic (MIA PaCa-2), and acute lymphoblastic leukemia (CCRF-CEM) cancer cell lines. A detailed structure–activity relationship study culminated in the identification of 3-N-benzo[1,2,5]oxadiazole 17 and 3-N-2-methylquinoline 20, whose IC50 values ranged from 328 to 644 nM against CCRF-CEM and MIA PaCa-2. Further mechanistic studies revealed that 20 caused cell cycle arrest at the S phase and induced apoptosis in CCRF-CEM cancer cells. These 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles may serve as a template for further optimization to afford more active analogs and develop a comprehensive understanding of the structure–activity relationships of indole anticancer molecules.

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Acknowledgements

We are grateful to the National Health Research Institutes and the National Science and Technology Council of Taiwan (105-2113-M-400-002) for financial support. We also thank Dr. Hsin-Ru Wu of the Instrumentation Center of National Tsing Hua University for HPLC MS measurements.

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Authors and Affiliations

  1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan

    Chun-Hsu Yao, Mine-Hsine Wu, Po-Wei Chang, Szu-Huei Wu, Jen-Shin Song, Hsing-Hao Huang, Yu-Chun Chen & Jinq-Chyi Lee

  2. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan

    Hsing-Hao Huang

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  1. Chun-Hsu Yao
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  2. Mine-Hsine Wu
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Contributions

C.-H.Y., P.-W.C., H.-H.H., and Y.-C.C. synthesized the desired indoles. M.-H.W. and S.-H.W. performed the biological activity evaluation and mechanistic studies. J-.S.S. supervised the experiments of biological activity evaluation and mechanistic studies. J.-C.L. designed the experiments, analyzed the data, supervised the project, and wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Jinq-Chyi Lee.

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Yao, CH., Wu, MH., Chang, PW. et al. Design, synthesis, and anticancer evaluation of 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles. Mol Divers 28, 595–608 (2024). https://doi.org/10.1007/s11030-023-10605-x

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  • DOI: https://doi.org/10.1007/s11030-023-10605-x

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