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

Chiao-Nien Chang; I-Chun Lin; Tzung-Sheng Lin; Pei-Fang Chiu; Yeh-Lin Lu; Manmath Narwane; I-Chen Liu; Yue Hng; Keng-Chang Tsai; Mei-Hsiang Lin; Yves S Y Hsieh; Mei-Jou Chen; Pi-Hui Liang

doi:10.1016/j.bioorg.2022.106148

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

Bioorg Chem. 2022 Dec:129:106148. doi: 10.1016/j.bioorg.2022.106148. Epub 2022 Oct 10.

Authors

Affiliations

¹ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; School of Pharmacy, National Taiwan University, Taiwan.
² School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
³ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
⁴ National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan.
⁵ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
⁶ School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Division of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Centre, Stockholm SE106 91, Sweden.
⁷ Department of Obstetrics and Gynecology and Livia Shangyu Wan Scholar, National Taiwan University Hospital, National Taiwan University, College of Medicine, Taipei 100, Taiwan.
⁸ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: phliang@ntu.edu.tw.

PMID: 36244324
DOI: 10.1016/j.bioorg.2022.106148

Abstract

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 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.

Keywords: Hormone dependent cancer; Irreversible Inhibitors; Steroid Sulfatase; Sulfamate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design*
Enzyme Inhibitors* / pharmacology
Female
Humans
Kinetics
MCF-7 Cells
Placenta* / enzymology
Pregnancy
Steryl-Sulfatase* / antagonists & inhibitors
Structure-Activity Relationship
Sulfonic Acids* / chemistry
Sulfonic Acids* / pharmacology

Substances

Enzyme Inhibitors
Steryl-Sulfatase
sulfamic acid
Sulfonic Acids