Design, Structure–Activity Relationships, and Enzyme Kinetic Studies of Tricyclic and Tetracyclic Coumarin–based Sulfamates as Steroid Sulfatase Inhibitors

Pei-Fang Chiu; I-Chun Lin; Yeh-Lin Lu; Chiao-Nien Chang; Hui-Yu Chan; Tzung-Shen Lin; Keng-Chang Tsai; Yves S. Y. Hsieh; Mei-Jou Chen; Mei-Hsiang Lin; Pi-Hui Liang

doi:10.1016/j.bioorg.2023.106581

Design, Structure–Activity Relationships, and Enzyme Kinetic Studies of Tricyclic and Tetracyclic Coumarin–based Sulfamates as Steroid Sulfatase Inhibitors

Pei-Fang Chiu, I-Chun Lin, Yeh-Lin Lu, Chiao-Nien Chang, Hui-Yu Chan, Tzung-Shen Lin, Keng-Chang Tsai, Yves S. Y. Hsieh, Mei-Jou Chen, Mei-Hsiang Lin, Pi-Hui Liang

研究成果: 雜誌貢獻 › 文章 › 同行評審

1 引文斯高帕斯（Scopus）

摘要

Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively.

原文	英語
文章編號	106581
期刊	Bioorganic Chemistry
卷	138
DOIs	https://doi.org/10.1016/j.bioorg.2023.106581
出版狀態	已發佈 - 9月 2023

ASJC Scopus subject areas

藥物發現
分子生物學
生物化學
有機化學

UN SDG

此研究成果有助於以下永續發展目標

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10.1016/j.bioorg.2023.106581

https://www.sciencedirect.com/science/article/pii/S0045206823002420

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Chiu, P.-F., Lin, I.-C., Lu, Y.-L., Chang, C.-N., Chan, H.-Y., Lin, T.-S., Tsai, K.-C., S. Y. Hsieh, Y., Chen, M.-J., Lin, M.-H., & Liang, P.-H. (2023). Design, Structure–Activity Relationships, and Enzyme Kinetic Studies of Tricyclic and Tetracyclic Coumarin–based Sulfamates as Steroid Sulfatase Inhibitors. Bioorganic Chemistry, 138, 文章 106581. https://doi.org/10.1016/j.bioorg.2023.106581

Chiu, P-F, Lin, I-C, Lu, Y-L, Chang, C-N, Chan, H-Y, Lin, T-S, Tsai, K-C, S. Y. Hsieh, Y, Chen, M-J, Lin, M-H & Liang, P-H 2023, 'Design, Structure–Activity Relationships, and Enzyme Kinetic Studies of Tricyclic and Tetracyclic Coumarin–based Sulfamates as Steroid Sulfatase Inhibitors', Bioorganic Chemistry, 卷 138, 106581. https://doi.org/10.1016/j.bioorg.2023.106581

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abstract = "Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively.",

keywords = "Coumarin, Hormone-dependent cancer, Irreversible inhibitors, Steroid sulfatase, Sulfamate",

author = "Pei-Fang Chiu and I-Chun Lin and Yeh-Lin Lu and Chiao-Nien Chang and Hui-Yu Chan and Tzung-Shen Lin and Keng-Chang Tsai and {S. Y. Hsieh}, Yves and Mei-Jou Chen and Mei-Hsiang Lin and Pi-Hui Liang",

note = "Funding Information: P.-F.C. is thankful for the scholarship from the XinChen Medical Research Foundation, Taiwan. Funding Information: This work was financially supported by the National Science and Technology Councils, Taiwan (104-2320-B-002-008-MY3, 107-2320-B-002-019-MY3, 108-3114-Y-001-002, 111-2628-B-002 -046 -; and 111-2622-8-002 -016 -TB1). Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = sep,

doi = "10.1016/j.bioorg.2023.106581",

language = "English",

volume = "138",

journal = "Bioorganic Chemistry",

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AU - Chiu, Pei-Fang

AU - Lin, I-Chun

AU - Lu, Yeh-Lin

AU - Chang, Chiao-Nien

AU - Chan, Hui-Yu

AU - Lin, Tzung-Shen

AU - Tsai, Keng-Chang

AU - S. Y. Hsieh, Yves

AU - Chen, Mei-Jou

AU - Lin, Mei-Hsiang

AU - Liang, Pi-Hui

N1 - Funding Information: P.-F.C. is thankful for the scholarship from the XinChen Medical Research Foundation, Taiwan. Funding Information: This work was financially supported by the National Science and Technology Councils, Taiwan (104-2320-B-002-008-MY3, 107-2320-B-002-019-MY3, 108-3114-Y-001-002, 111-2628-B-002 -046 -; and 111-2622-8-002 -016 -TB1). Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/9

Y1 - 2023/9

N2 - Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively.

AB - Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively.

KW - Coumarin

KW - Hormone-dependent cancer

KW - Irreversible inhibitors

KW - Steroid sulfatase

KW - Sulfamate

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JO - Bioorganic Chemistry

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Design, Structure–Activity Relationships, and Enzyme Kinetic Studies of Tricyclic and Tetracyclic Coumarin–based Sulfamates as Steroid Sulfatase Inhibitors

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ASJC Scopus subject areas

UN SDG

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