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Compounds 3j inhibited human placenta steroid sulfatse with IC 50 of 0.13 μM and displayed ireversible kinetic of K I 0.08 μM and K in cat 158 min−1. • Nineteen 3-aminocoumarin-7- O -sulfamates were designed and synthesized. • SAR revealed that modification at 3-position of coumarin resulted in enhancing STS inhibition. • Substitution at benzyl of 3-benzyl-aminocoumarin-7- O -sulfamates was crucial for STS inhibition. • Compound 3j inhibited STS from human placenta (IC 50 130 nM) and MCF-7 (IC 50 1.35 µM). Steroid sulfatase (STS) is a sulfatase enzyme that catalyzes the conversion of sulfated steroid precursors to free steroid. The inhibition of STS could abate estrogenic steroids that stimulate the proliferation and development of breast cancer, and therefore STS is a potential target for adjuvant endocrine therapy. In this study, a series of 3-benzylaminocoumarin-7- O -sulfamate derivatives targeting STS were designed and synthesized. Structure-relationship activities (SAR) analysis revealed that attachment of a benzylamino group at the 3-position of coumarin improved inhibitory activity. Compound 3j was found to have the highest inhibition activity against human placenta isolated STS (IC 50 0.13 μM) and MCF-7 cell lines (IC 50 1.35 µM). Kinetic studies found compound 3j to be an irreversible inhibitor of STS, with K I and k inact value of 86.9 nM and 158.7 min−1, respectively. [ABSTRACT FROM AUTHOR]

[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 k inact / K I of 28.6 and 19.1 nM−1min−1 on human STS, respectively. • Cytotoxicity of 9e (IC 50 of 0.65 µM) and 10c (IC 50 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 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of 32 tricyclic sulfamates as STS irreversible inhibitors. • SAR studies revealed that adjacent halogen-bearing phenyl gave the best inhibition. • 19 m , 19v , and 19w , had K I of 0.02 to 0.11 nM against STS. • Cellular potency is significant correlated with covalent kinetics (k inact/ K I). Steroid 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 19 m , 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 19 m , 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. [ABSTRACT FROM AUTHOR]