Chang, Chiao-NienChiao-NienChangLin, I-ChunI-ChunLinLin, Tzung-ShengTzung-ShengLinChiu, Pei-FangPei-FangChiuLu, Yeh-LinYeh-LinLuNarwane, ManmathManmathNarwaneLiu, I-ChenI-ChenLiuHng, YueYueHngTsai, Keng-ChangKeng-ChangTsaiLin, Mei-HsiangMei-HsiangLinS Y Hsieh, YvesYvesS Y HsiehMEI-JOU CHENPI-HUI LIANG2022-12-152022-12-152022-120045-2068https://scholars.lib.ntu.edu.tw/handle/123456789/626465Steroid sulfatase inhibitors block the local production of estrogenic steroids and are attractive agents for the treatment of estrogen-dependent cancers. Inspiration of coumarin-based inhibitors, we synthesized thirty-two 5-oxa-1,2,3,4-tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates, focusing on the substitution derivatives on the adjacent phenyl ring and evaluated their abilities to block STS from human placenta and MCF-7 cells. SAR analysis revealed that the incorporation of chlorine at either meta and/or para position of the adjacent phenyl ring of the tricyclic skeleton enhanced STS inhibition. Di-substitutions at the adjacent phenyl ring were superior to mono and tri-substitutions. Further kinetic analysis of these compounds revealed that chloride-bearing compounds, such as 19m, 19v, and 19w, had K_I of 0.02 to 0.11 nM and k_inact/K_I ratios of 8.8-17.5 nM^-1min^-¹, a parameter indicated for the efficiency of irreversible inhibition. We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19m, 19v, and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75-1 cell, which was a hormone-dependent cancer cell line with high STS expression.enHormone dependent cancer; Irreversible Inhibitors; Steroid Sulfatase; Sulfamate[SDGs]SDG3journal article10.1016/j.bioorg.2022.106148362443242-s2.0-85141890604WOS:000876730900007https://api.elsevier.com/content/abstract/scopus_id/85141890604