Sweeney Martin, Coyle Robert, Kavanagh Paul, Berezin Andrey A, Lo Re Daniele, Zissimou Georgia A, Koutentis Panayiotis A, Carty Michael P, Aldabbagh Fawaz
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Department of Chemistry, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
Bioorg Med Chem. 2016 Aug 15;24(16):3565-70. doi: 10.1016/j.bmc.2016.05.066. Epub 2016 May 30.
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.
硫氧还蛋白（Trx）-硫氧还蛋白还原酶（TrxR）系统在维持细胞氧化还原平衡中起关键作用，其中Trx在多种癌症中过度表达。抑制TrxR是抗癌药物研发的一项重要策略。天然产物侧耳素是一种著名的TrxR不可逆抑制剂。使用美国国立癌症研究所的COMPARE分析，苯并[1,2,4]三嗪-7-酮的细胞毒性数据与侧耳素显示出很强的相关性（皮尔逊相关系数约为0.8）。一种新的3-CF3取代的苯并[1,2,4]三嗪-7-酮对TrxR的抑制作用达到亚微摩尔级别，尽管母体化合物1,3-二苯基苯并[1,2,4]三嗪-7-酮对癌细胞系的细胞毒性更强。苯并[1,2,4]三嗪-7-酮对TrxR表现出不同类型的可逆抑制作用，循环伏安法显示出特征性的准可逆氧化还原过程。细胞活力研究表明，细胞毒性强烈依赖于1,3-二苯基苯并[1,2,4]三嗪-7-酮环6位的取代情况。
