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

• Published in: Bioorganic chemistry 2023-09, Vol.138, p.106581-106581, Article 106581
• Main Authors: Chiu, Pei-Fang, Lin, I-Chun, Lu, Yeh-Lin, Chang, Chiao-Nien, Chan, Hui-Yu, Lin, Tzung-Shen, Tsai, Keng-Chang, Hsieh, Yves S.Y., Chen, Mei-Jou, Lin, Mei-Hsiang, Liang, Pi-Hui
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - drug therapy; Coumarin; Coumarins - pharmacology; Coumarins - therapeutic use; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Hormone-dependent cancer; Humans; Irreversible inhibitors; Kinetics; Pregnancy; Steroid sulfatase; Steryl-Sulfatase; Structure-Activity Relationship; Sulfamate; Sulfonic Acids
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106581

[Display omitted] •Synthesis of 21 tricyclic and tetracyclic sulfamates as STS inhibitors.•Design novel nonsteroidal tetracyclic coumarin skeleton for STS inhibition.•Para substitutions at the phenyl ring of tricyclic analogs gave the best STS inhibition.•9e and 10c had kinact/KI of 28.6 and 19.1 nM−1min−1 on human STS, respectively.•Cytotoxicity of 9e (IC50 of 0.65 µM) and 10c (IC50 of 4.7 µM) on T-47D cells. 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.