Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors

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

doi:10.1016/j.bioorg.2020.103618

Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors

Bioorg Chem. 2020 Mar:96:103618. doi: 10.1016/j.bioorg.2020.103618. Epub 2020 Jan 27.

Authors

Affiliations

¹ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
² School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
³ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
⁴ National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan.
⁵ Department of Obstetrics and Gynecology and Livia Shangyu Wan Scholar, National Taiwan University Hospital, National Taiwan University, College of Medicine, Taipei 100, Taiwan.
⁶ School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Genomics Research Center, Academia Sinica, Taipei 128, Taiwan. Electronic address: phliang@ntu.edu.tw.

PMID: 32059152
DOI: 10.1016/j.bioorg.2020.103618

Abstract

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 (IC₅₀ 0.13 μM) and MCF-7 cell lines (IC₅₀ 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.

Keywords: Breast cancer; Coumarin; Hormone dependent cancer; Irreversible inhibitors; Steroid sulfatase; Sulfamate.

Publication types

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

MeSH terms

Amination
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology
Coumarins / chemical synthesis
Coumarins / chemistry*
Coumarins / pharmacology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Female
Humans
MCF-7 Cells
Placenta / enzymology
Pregnancy
Steryl-Sulfatase / antagonists & inhibitors*
Steryl-Sulfatase / metabolism
Structure-Activity Relationship
Sulfonic Acids / chemical synthesis
Sulfonic Acids / chemistry
Sulfonic Acids / pharmacology

Substances

Benzyl Compounds
Coumarins
Enzyme Inhibitors
Sulfonic Acids
sulfamic acid
STS protein, human
Steryl-Sulfatase