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

Bioorg Chem. 2023 Sep:138:106581. doi: 10.1016/j.bioorg.2023.106581. Epub 2023 May 6.

Authors

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 K_I of 0.05 and 0.4 nM, and k_inact/K_I 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / drug therapy
Coumarins / pharmacology
Coumarins / therapeutic use
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Female
Humans
Kinetics
Pregnancy
Steryl-Sulfatase*
Structure-Activity Relationship
Sulfonic Acids

Substances

Steryl-Sulfatase
sulfamic acid
Sulfonic Acids
Coumarins
Enzyme Inhibitors