Combinatorial synthesis, in silico, molecular and biochemical studies of tetrazole-derived organic selenides with increased selectivity against hepatocellular carcinoma
| Autor: | Abeer M. Ashmawy, Ludger A. Wessjohann, Amr Negm, Dalia M Ahmed, Saad Shaaban |
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| Rok vydání: | 2016 |
| Předmět: |
Thioredoxin Reductase 1
Carcinoma Hepatocellular DNA damage Tetrazoles Antineoplastic Agents Chemistry Techniques Synthetic 010402 general chemistry 01 natural sciences Antioxidants chemistry.chemical_compound Protein Domains Cell Line Tumor Organoselenium Compounds Drug Discovery Cytotoxic T cell Humans Tetrazole Computer Simulation Cytotoxicity Pharmacology chemistry.chemical_classification 010405 organic chemistry Ebselen Glutathione peroxidase Organic Chemistry Liver Neoplasms General Medicine 0104 chemical sciences Quinone Molecular Docking Simulation Biochemistry chemistry Cancer cell |
| Zdroj: | European journal of medicinal chemistry. 122 |
| ISSN: | 1768-3254 |
| Popis: | Novel tetrazole-based diselenides and selenoquinones were synthesized via azido-Ugi and sequential nucleophilic substitution (SN) strategy. Molecular docking study into mammalian TrxR1 was used to predict the anticancer potential of the newly synthesized compounds. The cytotoxic activity of the compounds was evaluated using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cancer cells and compared with their cytotoxicity in normal fibroblast (WI-38) cells. The corresponding redox properties of the synthesized compounds were assessed employing 2,2-diphenyl-1-picrylhydrazyl (DPPH), glutathione peroxidase (GPx)-like activity and bleomycin dependent DNA damage. In general, diselenides showed preferential cytotoxicity to HepG2 compared to MCF-7 cells. These compounds exhibited also good GPx catalytic activity compared to ebselen (up to 5 fold). Selenoquinones 18, 21, 22 and 23 were selected to monitor the expression levels of caspase-8, Bcl-2 and Ki-67 molecular biomarkers. Interestingly, these compounds downregulated the Bcl-2 and Ki-67 expression levels and activated the expression of caspase-8 in HepG2 cells compared to untreated cells. These results indicate that some of the newly synthesized compounds possess anti-HepG2 activity. |
| Databáze: | OpenAIRE |
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