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Sweeney, M,Coyle, R,Kavanagh, P,Berezin, AA,Lo Re, D,Zissimou, GA,Koutentis, PA,Carty, MP,Aldabbagh, F
Bioorgan Med Chem
Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition
WOS: 7 ()
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Anti-tumor Bioreduction Heterocyclic compound NCI-DTP COMPARE program TOXICITY GROWTH ASSAY LEAD
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]wtriazin-7-ones showed very strong correlation (Pearson correlation coefficients similar to 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. (C) 2016 Elsevier Ltd. All rights reserved.
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