title: Combinatorial synthesis, in silico, molecular and biochemical studies of tetrazole-derived organic selenides with increased selectivity against hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Organic Chemistry Division, Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhorya Street, 35516 Mansoura, Egypt; Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, D-06120 Halle (Saale), Germany. Electronic address: dr_saad_chem@mans.edu.eg.
authors.forename: Saad
authors.initials: S
authors.lastname: Shaaban
authors.affiliation: Biochemistry Division, Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhorya Street, 35516 Mansoura, Egypt.
authors.forename: Amr
authors.initials: A
authors.lastname: Negm
authors.affiliation: Cancer Biology Department, National Cancer Institute, Cairo University, Egypt.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Ashmawy
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Egypt.
authors.forename: Dalia M
authors.initials: DM
authors.lastname: Ahmed
authors.affiliation: Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, D-06120 Halle (Saale), Germany. Electronic address: wessjohann@ipb-halle.de.
authors.forename: Ludger A
authors.initials: LA
authors.lastname: Wessjohann
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D062105:Molecular Docking Simulation; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000072417:Protein Domains; D013777:Tetrazoles / Q000737:chemistry*; D054481:Thioredoxin Reductase 1 / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016566:Organoselenium Compounds; D013777:Tetrazoles; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1
keywords: Apoptosis; Azido-Ugi reaction; Bcl-2; Caspase-8; Diselenides; Ki-67; Organoselenium; Quinone; Redox modulators; Tetrazole