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

8 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

Fingerprint

Thioredoxin-Disulfide Reductase
Thioredoxins
Neoplasms
Cytotoxicity
Oxidation-Reduction
Cells
National Cancer Institute (U.S.)
Drug Discovery
Biological Products
Cyclic voltammetry
Cell Survival
Substitution reactions
pleurotin
Cell Line

Keywords

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

Cite this

Sweeney, Martin ; Coyle, Robert ; Kavanagh, Paul ; Berezin, Andrey A. ; Lo Re, Daniele ; Zissimou, Georgia A. ; Koutentis, Panayiotis A. ; Carty, Michael P. ; Aldabbagh, Fawaz. / Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition. In: Bioorganic & Medicinal Chemistry. 2016 ; Vol. 24, No. 16. pp. 3565-3570.
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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 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.",
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Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition. / Sweeney, Martin; Coyle, Robert; Kavanagh, Paul; Berezin, Andrey A.; Lo Re, Daniele; Zissimou, Georgia A.; Koutentis, Panayiotis A.; Carty, Michael P.; Aldabbagh, Fawaz.

In: Bioorganic & Medicinal Chemistry, Vol. 24, No. 16, 15.08.2016, p. 3565-3570.

Research output: Contribution to journalArticle

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AU - Sweeney, Martin

AU - Coyle, Robert

AU - Kavanagh, Paul

AU - Berezin, Andrey A.

AU - Lo Re, Daniele

AU - Zissimou, Georgia A.

AU - Koutentis, Panayiotis A.

AU - Carty, Michael P.

AU - Aldabbagh, Fawaz

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