Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition
| Autor: | Sweeney, M., Coyle, R., Kavanagh, P., Berezin, Andrey A., Lo Re, D., Zissimou, Georgia A., Koutentis, Panayiotis Andreas, Carty, Michael P., Aldabbagh, Fawaz |
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| Přispěvatelé: | ~|6201984|~, Koutentis, Panayiotis Andreas [0000-0002-4652-7567], Zissimou, Georgia A. [0000-0003-4821-9469] |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Bioreduction
Thioredoxin reductase 1 3 diphenylbenzo[1 2 4]triazin 7 one 6 (methylamino) 1 3 diphenylbenzo[1 2 4]triazin 7 one Clinical Biochemistry Pharmaceutical Science triazine derivative Reductase NCI-DTP COMPARE program 01 natural sciences Biochemistry Anti-tumor chemistry.chemical_compound Drug Discovery Cytotoxicity Chimie pharmaceutique Périodiques enzyme inhibition antineoplastic agent Cell Line Transformed chemistry.chemical_classification Heterocyclic compound MTT assay Triazines drug cytotoxicity thioredoxin reductase n (7 oxo 1 3 diphenyl 1 7 dihydrobenzo[1 2 4]triazin 6 yl)acetamide unclassified drug 1 phenyl 3 (trifluoromethyl)benzo[1 2 4]triazin 7 one 6 morpholino 1 3 diphenylbenzo[1 2 4]triazin 7 one Thioredoxin-Disulfide Reductase 6 (diethylamino) 1 3 diphenylbenzo[1 2 4]triazin 7 one 6 ethoxy 1 3 diphenylbenzo[1 2 4]triazin 7 one Molecular Medicine Thioredoxin 1 3 diphenyl 6 (pyrrolidin 1 yl)benzo[1 2 4]triazin 7 one cancer cell line Stereochemistry growth Chemistry Organic cyclic potentiometry Antineoplastic Agents 010402 general chemistry 6 methoxy 1 3 diphenylbenzo[1 2 4]triazin 7 one chemistry 1 2 4 benzotriazine derivative Heterocyclic Compounds 4 or More Rings Article Chimie bio-organique Humans transformed cell line controlled study Viability assay human drug screening Molecular Biology anthracene derivative antagonists and inhibitors lead Natural product Bioorganic chemistry 010405 organic chemistry 6 (ethylamino) 1 3 diphenylbenzo[1 2 4]triazin 7 one human cell Organic Chemistry fused heterocyclic rings toxicity assay drug development 6 amino 1 3 diphenylbenzo[1 2 4]triazin 7 one 0104 chemical sciences 1 3 diphenyl 6 (piperidin 1 yl)benzo[1 2 4]triazin 7 one Chemistry Clinical Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization drug synthesis 1 3 diphenyl 6 thiomorpholinobenzo[1 2 4]triazin 7 one matrix-assisted laser desorption-ionization mass spectrometry benzo[1 2 4]triazin 7 one derivative Drug Screening Assays Antitumor Pharmaceutical chemistry oxidation reduction reaction pleurotin biological |
| Zdroj: | Bioorganic and Medicinal Chemistry Bioorg.Med.Chem. |
| ISSN: | 0968-0896 |
| Popis: | The thioredoxin (Trx)-thioredoxin reductase (TrxR) system plays a key role in maintaining the cellular redox balance with Trx being over-expressed in a number of cancers. Inhibition of TrxR is an important strategy for anti-cancer drug discovery. The natural product pleurotin is a well-known irreversible inhibitor of TrxR. The cytotoxicity data for benzo[1,2,4]triazin-7-ones showed very strong correlation (Pearson correlation coefficients ~0.8) to pleurotin using National Cancer Institute COMPARE analysis. A new 3-CF3 substituted benzo[1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo[1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo[1,2,4]triazin-7-ones exhibited different types of reversible inhibition of TrxR, and cyclic voltammetry showed characteristic quasi-reversible redox processes. Cell viability studies indicated strong dependence of cytotoxicity on substitution at the 6-position of the 1,3-diphenylbenzo[1,2,4]triazin-7-one ring. F.A. thanks the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for Martin Sweeney and College of Science, National University of Ireland Galway (NUI Galway) for a postgraduate scholarship for Robert Coyle. We thank the National Cancer Institute (USA), Development Therapeutic Program for providing us with a small quantity of pleurotin. P.A.K. thanks the Cyprus Research Promotion Foundation [Grants: NEAYPODOMH/NEKYP/0308/02 and YGEIA/BIOS/0308(BIE)/13], the University of Cyprus (Medium Sized Grant), and the following organizations in Cyprus for generous donations of chemicals and glassware: the State General Laboratory, the Agricultural Research Institute, the Ministry of Agriculture, Medochemie Ltd and Biotronics Ltd. Furthermore, P.A.K. thanks the A. G. Leventis Foundation for helping to establish the NMR facility in the University of Cyprus. peer-reviewed 2018-05-30 |
| Databáze: | OpenAIRE |
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