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

Martin Sweeney, Robert Coyle, Paul Kavanagh, Andrey A. Berezin, Daniele Lo Re, Georgia A. Zissimou, Panayiotis A. Koutentis, Michael P. Carty*, Fawaz Aldabbagh

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

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-CF3substituted 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.

Original languageEnglish
Pages (from-to)3565-3570
JournalBioorganic & Medicinal Chemistry
Volume24
Issue number16
Early online date30 May 2016
DOIs
Publication statusPublished - 15 Aug 2016

Keywords

  • Anti-tumor
  • Bioreduction
  • Heterocyclic compound
  • NCI-DTP COMPARE program

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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