Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors - Publikacja - MOST Wiedzy

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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

Abstrakt

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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Kategoria:
Publikacja w czasopiśmie
Typ:
artykuł w czasopiśmie wyróżnionym w JCR
Opublikowano w:
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY nr 128, strony 79 - 87,
ISSN: 0223-5234
Język:
angielski
Rok wydania:
2017
Opis bibliograficzny:
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:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1016/j.ejmech.2017.01.028
Weryfikacja:
Politechnika Gdańska

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