Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition |
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| Institution: | 1. School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland;2. Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus;3. Centre of Chromosome Biology, Biochemistry, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland;1. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, Andhra Pradesh 500 037, India;2. National Center for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India;1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;2. Division of Hematology, University of Colorado, Aurora, CO 80045, USA;3. Department of Radiology and Neurology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;1. Molecular Electronics and Photonics Research Unit, Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, 3603 Limassol, Cyprus;2. Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus;1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People’s Republic of China;2. College of Life Sciences, Nankai University, Tianjin 300353, People’s Republic of China;3. Accendatech Company, Ltd., Tianjin 300384, People’s Republic of China |
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| Abstract: | 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 benzo1,2,4]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 benzo1,2,4]triazin-7-one gave submicromolar inhibition of TrxR, although the parent compound 1,3-diphenylbenzo1,2,4]triazin-7-one was more cytotoxic against cancer cell lines. Benzo1,2,4]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-diphenylbenzo1,2,4]triazin-7-one ring. |
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| Keywords: | Anti-tumor Bioreduction Heterocyclic compound NCI-DTP COMPARE program |
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