Betulin-1,4-quinone hybrids: Synthesis, anticancer activity and molecular docking study with NQO1 enzyme.
Autor: | Kadela-Tomanek M; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland. Electronic address: mkadela@sum.edu.pl., Bębenek E; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland., Chrobak E; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland., Marciniec K; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland., Latocha M; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Cell Biology, 8 Jedności Str., 41-200 Sosnowiec, Poland., Kuśmierz D; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Cell Biology, 8 Jedności Str., 41-200 Sosnowiec, Poland., Jastrzębska M; Silesian Center for Education and Interdisciplinary Research, University of Silesia, Institute of Physics, Department of Solid State Physics, 75 Pułku Piechoty 1a, 41-500 Chorzów, Poland., Boryczka S; Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Organic Chemistry, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland. |
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Jazyk: | angličtina |
Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2019 Sep 01; Vol. 177, pp. 302-315. Date of Electronic Publication: 2019 May 24. |
DOI: | 10.1016/j.ejmech.2019.05.063 |
Abstrakt: | Betulin-1,4-quinone hybrids were obtain by connecting two active structures with a linker. This strategy allows for obtaining compounds showing a high biological activity and better bioavailability. In this research, synthesis, anticancer activity and molecular docking study of betulin-1,4-quinone hybrids are presented. Newly synthesized compounds were characterized by 1 H, 13 C NMR, IR and HR-MS. Hybrids were tested in vitro against a panel of human cell lines including glioblastoma, melanoma, breast and lung cancer. They showed a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activities of the studied hybrids were increasing against the cell line with higher NQO1 protein level, like melanoma (C-32), breast (MCF-7) and lung (A-549) cancer. Selected hybrids were tested on the transcriptional activity of the gene encoding a proliferation marker (H3 histone), a cell cycle regulators (p53 and p21) and an apoptosis pathway (BCL-2 and BAX). The obtained results suggested that the tested compounds caused a mitochondrial apoptosis pathway in A549 and MCF-7 cell lines. The molecular docking was used to examine the probable interaction between the hybrids and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the type of the 1,4-quinone moiety affected the location of the compound in the active site of the enzyme. Moreover, it was shown that an interaction of 1,4-quinone fragment with the hydrophobic matrix of the active site near Tyr128, Phe178, Trp105 and FAD cofactor could explain the observed increase of TP53 gene expression. (Copyright © 2019 Elsevier Masson SAS. All rights reserved.) |
Databáze: | MEDLINE |
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