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The Design, Structure–Activity, and Kinetic Studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl Sulfamates as Steroid Sulfatase Inhibitors
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2022 (English)In: Bioorganic chemistry, ISSN 0045-2068, article id 106148Article in journal (Refereed) Published
Abstract [en]

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 19m, 19v, and 19w, had KI of 0.02 to 0.11 nM and kinact/KI 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.

Place, publisher, year, edition, pages
Elsevier BV , 2022. article id 106148
Keywords [en]
Steroid Sulfatase, Sulfamate, Hormone dependent cancer, Irreversible Inhibitors
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-320098DOI: 10.1016/j.bioorg.2022.106148ISI: 000876730900007PubMedID: 36244324Scopus ID: 2-s2.0-85141890604OAI: oai:DiVA.org:kth-320098DiVA, id: diva2:1703614
Note

QC 20221017

Available from: 2022-10-14 Created: 2022-10-14 Last updated: 2023-06-08Bibliographically approved

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Publisher's full textPubMedScopushttps://www.sciencedirect.com/science/article/pii/S0045206822005545

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Hsieh, Yves S. Y.

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