Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 16; pp. 3565 - 3570
• Main Authors: Sweeney, Martin, Coyle, Robert, Kavanagh, Paul, Berezin, Andrey A., Lo Re, Daniele, Zissimou, Georgia A., Koutentis, Panayiotis A., Carty, Michael P., Aldabbagh, Fawaz
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-08-2016
• Subjects: Anti-tumor; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bioreduction; Cell Line, Transformed; Drug Discovery; Drug Screening Assays, Antitumor; Heterocyclic compound; Heterocyclic Compounds, 4 or More Rings - antagonists & inhibitors; Humans; NCI-DTP COMPARE program; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Triazines - chemistry; Triazines - pharmacology; Bioreduction; Anti-tumor; Heterocyclic compound; NCI-DTP COMPARE program
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.05.066

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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.