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 journalArticlepeer-review

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 languageEnglish
Article number106581
JournalBioorganic Chemistry
Volume138
DOIs
Publication statusPublished - Sept 2023

Keywords

  • Coumarin
  • Hormone-dependent cancer
  • Irreversible inhibitors
  • Steroid sulfatase
  • Sulfamate

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Biology
  • Biochemistry
  • Organic Chemistry

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