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

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

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Article number	103618
Journal	Bioorganic Chemistry
Volume	96
DOIs	https://doi.org/10.1016/j.bioorg.2020.103618
Publication status	Published - Mar 2020

Keywords

Breast cancer
Coumarin
Hormone dependent cancer
Irreversible inhibitors
Steroid sulfatase
Sulfamate

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bioorg.2020.103618

Cite this

@article{7321bd1379054cbd80f838a581c0a86f,

title = "Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors",

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 KI and kinact value of 86.9 nM and 158.7 min−1, respectively.",

keywords = "Breast cancer, Coumarin, Hormone dependent cancer, Irreversible inhibitors, Steroid sulfatase, Sulfamate",

author = "Yue Hng and Lin, {Mei Hsiang} and Lin, {Tzung Sheng} and Liu, {I. Chen} and Lin, {I. Chun} and Lu, {Yeh Lin} and Chang, {Chiao Nien} and Chiu, {Pei Fang} and Tsai, {Keng Chang} and Chen, {Mei Jou} and Liang, {Pi Hui}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = mar,

doi = "10.1016/j.bioorg.2020.103618",

language = "English",

volume = "96",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors

AU - Hng, Yue

AU - Lin, Mei Hsiang

AU - Lin, Tzung Sheng

AU - Liu, I. Chen

AU - Lin, I. Chun

AU - Lu, Yeh Lin

AU - Chang, Chiao Nien

AU - Chiu, Pei Fang

AU - Tsai, Keng Chang

AU - Chen, Mei Jou

AU - Liang, Pi Hui

PY - 2020/3

Y1 - 2020/3

N2 - 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 KI and kinact value of 86.9 nM and 158.7 min−1, respectively.

AB - 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 KI and kinact value of 86.9 nM and 158.7 min−1, respectively.

KW - Breast cancer

KW - Coumarin

KW - Hormone dependent cancer

KW - Irreversible inhibitors

KW - Steroid sulfatase

KW - Sulfamate

UR - http://www.scopus.com/inward/record.url?scp=85079181535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85079181535&partnerID=8YFLogxK

U2 - 10.1016/j.bioorg.2020.103618

DO - 10.1016/j.bioorg.2020.103618

M3 - Article

AN - SCOPUS:85079181535

SN - 0045-2068

VL - 96

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 103618

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this