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 language | English |
|---|---|
| Pages (from-to) | 3565-3570 |
| Journal | Bioorganic & Medicinal Chemistry |
| Volume | 24 |
| Issue number | 16 |
| Early online date | 30 May 2016 |
| DOIs | |
| Publication status | Published - 15 Aug 2016 |
Fingerprint
Keywords
- Anti-tumor
- Bioreduction
- Heterocyclic compound
- NCI-DTP COMPARE program
Cite this
}
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 journal › Article
TY - JOUR
T1 - Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition
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
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
KW - Anti-tumor
KW - Bioreduction
KW - Heterocyclic compound
KW - NCI-DTP COMPARE program
UR - http://www.scopus.com/inward/record.url?scp=84973558703&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2016.05.066
DO - 10.1016/j.bmc.2016.05.066
M3 - Article
AN - SCOPUS:84973558703
VL - 24
SP - 3565
EP - 3570
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 16
ER -