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

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Article number	106581
Journal	Bioorganic Chemistry
Volume	138
DOIs	https://doi.org/10.1016/j.bioorg.2023.106581
Publication status	Published - Sept 2023

Keywords

Coumarin
Hormone-dependent cancer
Irreversible inhibitors
Steroid sulfatase
Sulfamate

ASJC Scopus subject areas

Drug Discovery
Molecular Biology
Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, Article 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, vol. 138, 106581. https://doi.org/10.1016/j.bioorg.2023.106581

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

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",

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

language = "English",

volume = "138",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

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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

JF - 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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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