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Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors
Abstract
In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta and against estrogen receptor-(ER)-positive MCF-7 and T47D cells, as well as ER-negative MDA-MB-231 and SkBr3 cancer cell lines. In the course of our investigation, compounds 6c and 6j demonstrated the highest inhibitory effect in enzymatic STS assays, both with IC50 values of 0.18 μM (the IC50 value of coumarin-7-O-sulfamate is 1.38 μM, used as a reference). Compound 6j exhibited the highest potency against the MCF-7 and T47D cell lines (15.9 μM and 8.7 μM, respectively). The GI50 values of tamoxifen (used as a reference) were 6.8; 10.6; 15.1; 12.5 μM against MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines, respectively. Despite the slightly lower activity of compounds 1 and 2 (both in enzymatic and cell-based experiments) compared to 6g and 6j, analogues 1 and 2 proved to selectively inhibit the growth of ER- and PR-positive cell lines.
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Authors (8)
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Maciej Masłyk
- Katolicki Uniwersytet Lubelski
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Konrad Kubiński
- Katolicki Uniwersytet Lubelski
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
no. 128,
pages 79 - 87,
ISSN: 0223-5234 - Language:
- English
- Publication year:
- 2017
- Bibliographic description:
- Daśko M., Przybyłowska M., Rachoń J., Masłyk M., Kubiński K., Misiak M., Składanowski A., Demkowicz S.: Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors// EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. -Vol. 128, (2017), s.79-87
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.ejmech.2017.01.028
- Verified by:
- Gdańsk University of Technology
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