Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors.
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 IC50values of 0.18 μM (the IC50value 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 GI50values 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.
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland. Electronic address: matdasko@gmail.com.
Mateusz
M
Daśko
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
Maja
M
Przybyłowska
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
Janusz
J
Rachon
Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland.
Maciej
M
Masłyk
Department of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, Konstantynów 1i, 20-708 Lublin, Poland.
Konrad
K
Kubiński
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
Majus
M
Misiak
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.
Andrzej
A
Składanowski
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland. Electronic address: sebdemko@pg.gda.pl.
Sebastian
S
Demkowicz
D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D054879:Halogenation; D006801:Humans; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000378:metabolism; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D014407:Tumor Cells, Cultured
C000616836:3-(4-(2-(2,5-bis-trifluoromethyl-phenyl)-acetylamino)-phenyl)-coumarin-7-O-sulfamate; C000616835:3-(4-(3,4-difluoro-benzoylamino)-phenyl)-coumarin-7-O-sulfamate; D003374:Coumarins; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D013449:Sulfonamides; C100462:coumarin 7-O-sulfamate; D043266:Steryl-Sulfatase
Breast cancer; Coumarin; STS inhibitors; Steroid sulfatase; Sulfamates