Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads.
Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads.
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DOI：
10.18632/oncotarget.9579
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Chew EH
中科院分区：
文献类型：
--
作者：
Kaminska KK;Bertrand HC;Tajima H;Stafford WC;Cheng Q;Chen W;Wells G;Arner ES;Chew EH
已知具有吲哚啉酮化学支架的几种化合物具有抗癌性质。例如，酪氨酸激酶抑制剂舒尼替尼是亚芳基吲哚啉-2-酮化合物。与吲哚啉酮化合物的结构修饰相关的化学多功能性是发现具有抗癌性质的其他衍生物的潜力的基础。先前合成的3-（2-氧代亚乙基）二氢吲哚-2-酮化合物，参考母体化合物1 [1-甲基-3（2-氧代亚丙基）二氢吲哚-2-酮]也称为超肉桂醛（SCA）化合物，带有氮连接的α，β-不饱和羰基（迈克尔受体）部分。在此，我们发现带有N-取代基的类似物，特别是分别带有N-丁基和N-苄基取代基的化合物4和5，对人HCT 116结肠直肠癌和MCF-7乳腺癌细胞具有强烈的细胞毒性。这些化合物还显示出很强的硫氧还蛋白还原酶（TrxR）抑制活性，这可能归因于迈克尔受体部分的亲电性。它们对细胞TrxR抑制相关抗氧化酶谷胱甘肽还原酶（GR）、硫氧还蛋白（Trx）和谷胱甘肽过氧化物酶（GPx）的选择性是通过靶向TrxR的高度可及的C-末端活性位点中的硒代半胱氨酸（Sec）残基来介导的。吲哚啉-2-酮化合物介导的TrxR抑制导致细胞Trx氧化，氧化应激增加和凋亡信号调节激酶1（ASK 1）的激活。这些事件还导致p38和JNK促分裂原活化蛋白激酶（MAPK）信号通路的激活，以及具有PARP裂解和半胱天冬酶3激活的凋亡特征的细胞死亡。总之，这些结果表明，特异性靶向TrxR的吲哚啉-2-酮类化合物可作为抗癌治疗的新型药物先导。
Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2-oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy.
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影响因子：
3.7
作者：
Anestål K;Prast-Nielsen S;Cenas N;Arnér ES
通讯作者：
Arnér ES
影响因子：
7.4
作者：
Chew, Eng-Hui;Nagle, Amrita A.;Westwell, Andrew D.
通讯作者：
Westwell, Andrew D.
DOI：
10.1016/0167-4781(94)90180-5
发表时间：
1994-08-02
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
GASDASKA, PY;OBLONG, JE;POWIS, G
通讯作者：
POWIS, G
影响因子：
3.3
作者：
Grogan, TM;Fenoglio-Prieser, C;Powis, G
通讯作者：
Powis, G
影响因子：
4.8
作者：
Chew, Eng-Hui;Lu, Jun;Holmgren, Arne
通讯作者：
Holmgren, Arne