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

Chiu, Pei-FangPei-FangChiuLin, I-ChunI-ChunLinLu, Yeh-LinYeh-LinLuChang, Chiao-NienChiao-NienChangChan, Hui-YuHui-YuChanLin, Tzung-ShenTzung-ShenLinTsai, Keng-ChangKeng-ChangTsaiHsieh, Yves S YYves S YHsiehMEI-JOU CHENLin, Mei-HsiangMei-HsiangLinPI-HUI LIANG2023-09-052023-09-052023-0900452068https://scholars.lib.ntu.edu.tw/handle/123456789/635023Inhibition 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.enCoumarin; Hormone-dependent cancer; Irreversible inhibitors; Steroid sulfatase; SulfamateDesign, structure-activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin-based sulfamates as steroid sulfatase inhibitorsjournal article10.1016/j.bioorg.2023.106581371724372-s2.0-85159049971https://api.elsevier.com/content/abstract/scopus_id/85159049971