Discovery of anti-cancer activity for benzo[1, 2, 4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Sweeney, Martin; Coyle, Robert; Kavanagh, Paul; Berezin, Andrey A.; Lo Re, Daniele; Zissimou, Georgia A.; Koutentis, Panayiotis A.; Carty, Michael P.; Aldabbagh, Fawaz
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 16(2016)
• Page Start: 3565
• Page End: 3570
• Publication Date: 2016-08-15
• Subjects: Anti-tumor -- Bioreduction -- Heterocyclic compound -- NCI-DTP COMPARE program; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.066
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 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.