| Autor: |
Szczęśniak-Sięga BM; Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland., Zaręba N; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland., Czyżnikowska Ż; Department of Basic Chemical Sciences, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland., Janek T; Department of Biotechnology and Food Microbiology, Faculty of Biotechnology and Food Science, Wroclaw University of Environmental and Life Sciences, Chełmońskiego 37, 51-630 Wroclaw, Poland., Kepinska M; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland. |
| Abstrakt: |
The aim of this study was to obtain new, safe, and effective compounds with anticancer activity since cancer is still the leading cause of mortality worldwide. The rational design of new compounds was based on the introduction of differentially substituted phenylpiperazines into the 1,2-benzothiazine scaffold as a reference for the structures of recent topoisomerase II (Topo II) inhibitors such as dexrazoxane and XK-469. The newly designed group of 1,2-benzothiazine derivatives was synthesized and tested on healthy (MCF10A) and cancer (MCF7) cell lines, alone and in combination with doxorubicin (DOX). In addition, molecular docking studies were performed both to the DNA-Topo II complex and to the minor groove of DNA. Most of the tested compounds showed cytotoxic activity comparable to doxorubicin, a well-known anticancer drug. The compound BS230 (3-(4-chlorobenzoyl)-2-{2-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-oxoethyl}-4-hydroxy-2 H -1,2-benzothiazine 1,1-dioxide) showed the best antitumor activity with lower cytotoxicity towards healthy cells and at the same time stronger cytotoxicity towards cancer cells than DOX. Moreover, molecular docking studies showed that BS230 has the ability to bind to both the DNA-Topo II complex and the minor groove of DNA. Binding of the minor groove to DNA was also proven by fluorescence spectroscopy. |
