2. Academic Validation
  3. Design, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitors

Design, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitors

  • Bioorg Chem. 2023 Sep;138:106581. doi: 10.1016/j.bioorg.2023.106581.
Pei-Fang Chiu 1,  I-Chun Lin 1,  Yeh-Lin Lu 2,  Chiao-Nien Chang 1,  Hui-Yu Chan 3,  Tzung-Shen Lin 1,  Keng-Chang Tsai 4,  Yves S Y Hsieh 5,  Mei-Jou Chen 6,  Mei-Hsiang Lin 7,  Pi-Hui Liang 8
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
  • 3 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
  • 4 National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taipei.
  • 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Division of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Centre, Stockholm SE106 91, Sweden.
  • 6 Department of Obstetrics and Gynecology and Livia Shangyu Wan Scholar, National Taiwan University Hospital, National Taiwan University, College of Medicine, Taipei 100, Taiwan.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: mhl00001@tmu.edu.tw.
  • 8 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: phliang@ntu.edu.tw.
PMID: 37172437 DOI: 10.1016/j.bioorg.2023.106581
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.

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