Repozytorium publikacji - Politechnika Gdańska

In the present work, we described convenient methods for the synthesis ofN-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase(STS) inhibitors. To design the structures of the potential STS inhibitors, molecularmodeling techniques were used. A computational docking method was used to deter-mine the binding modes of the synthesized inhibitors as well as to identify potentialinteractions between specified functional groups on the inhibitors and the amino acidresidues present in the active site of the enzyme. The inhibitory activities of the syn-thesized compounds were tested in an enzymatic assay with STS isolated from ahuman placenta. Within the set of newly synthesized compounds,9edemonstratedthe highest inhibitory activity in the enzymatic assay with an IC50value of 0.201μM(the IC50value of667-COUMATEin the same test was 0.062μM). Furthermore, wetried to verify if the obtained STS inhibitors are able to pass through the cellular mem-brane effectively in cell line experiments. In the course of our study, we determinedthe STS activity in the MCF-7 cell line after incubation in the presence of the inhibitors(at 100 nM concentration). For this evaluation, we included newly synthesized com-pounds9a-gand theirN-phosphorylated analogs6a-h, whose synthesis has been pre-viously described. We found that the lowest STS activities were measured in thepresence ofN-phosphorylated derivatives6e(0.1% of STS activity) and6f(0.2% ofSTS activity). The measured STS activity in the presence of667-COUMATE(used as areference) was 0.1%. Moreover, at concentrations up to 1μM, the most active com-pounds (6e,6f,9b,and9e) did not exert any toxic effects on zebrafish embryos.

Autorzy

• dr inż. Mateusz Daśko link otwiera się w nowej karcie ,
• dr hab. inż. Sebastian Demkowicz link otwiera się w nowej karcie ,
• dr inż. Karol Biernacki link otwiera się w nowej karcie ,
• Amira Harrous link otwiera się w nowej karcie ,
• prof. dr hab. inż. Janusz Rachoń link otwiera się w nowej karcie ,
• Witold Kozak link otwiera się w nowej karcie ,
• Aleksandra Martyna,
• Maciej Masłyk,
• Konrad Kubiński,
• Anna Boguszewska‐Czubara