Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition.
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.
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Martin
M
Sweeney
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Robert
R
Coyle
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Paul
P
Kavanagh
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
Andrey A
AA
Berezin
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
Daniele
D
Lo Re
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
Georgia A
GA
Zissimou
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
Panayiotis A
PA
Koutentis
Centre of Chromosome Biology, Biochemistry, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland. Electronic address: michael.carty@nuigalway.ie.
Michael P
MP
Carty
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland. Electronic address: fawaz.aldabbagh@nuigalway.ie.
Fawaz
F
Aldabbagh
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000037:antagonists & inhibitors*; D006801:Humans; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D014227:Triazines; D013880:Thioredoxin-Disulfide Reductase; C479485:pleurotin
Anti-tumor; Bioreduction; Heterocyclic compound; NCI-DTP COMPARE program