1. Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors.
- Author
-
Hng Y, Lin MH, Lin TS, Liu IC, Lin IC, Lu YL, Chang CN, Chiu PF, Tsai KC, Chen MJ, and Liang PH
- Subjects
- Amination, Benzyl Compounds chemical synthesis, Benzyl Compounds chemistry, Benzyl Compounds pharmacology, Coumarins chemical synthesis, Enzyme Inhibitors chemical synthesis, Female, Humans, MCF-7 Cells, Placenta enzymology, Pregnancy, Steryl-Sulfatase metabolism, Structure-Activity Relationship, Sulfonic Acids chemical synthesis, Sulfonic Acids chemistry, Sulfonic Acids pharmacology, Coumarins chemistry, Coumarins pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Steryl-Sulfatase antagonists & 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 (IC
50 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF