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Evaluation of catacholase mimicking activity and apoptosis in human colorectal carcinoma cell line by activating mitochondrial pathway of copper(II) complex coupled with 2-(quinolin-8-yloxy)(methyl)benzonitrile and 8-hydroxyquinoline
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-11-21 , DOI: 10.1016/j.bioorg.2020.104479
Arif Ali 1 , Snehasis Mishra 2 , Saima Kamaal 1 , Abdullah Alarifi 3 , Mohd Afzal 3 , Krishna Das Saha 2 , Musheer Ahmad 1
Affiliation  

To evaluate the cytotoxic potential of metal-based chemotherapeutic candidate towards the colorectal cancer, we have synthesized a new copper(II) complex [Cu(qmbn)(q)(Cl)] (1) (where, qmbn = 2-(quinolin-8-yloxy)(methyl)benzonitrile and q = 8-hydroxyquinoline) and structurally characterized by single crystal X-ray, Powder-XRD, FTIR and thermogravimetric analysis (TGA). The structural analysis reveals that copper(II) ions exist in a distorted square pyramidal (τ = ∼0.1), with ligation of a chloride ion, oxygen atom and two nitrogen atoms at equatorial position and one oxygen atom at apical position. The cytotoxicity potential of complex 1 was executed against human colorectal cell lines (HCT116), which showed that 1 induces mitochondrion-mediated apoptotic cell death via activation of the Bax (pro-apoptotic protein) caspases-3 and 9 proteins. Interestingly, complex 1 was found to be a good candidate as electron-transfer catalyst which mimics catacholase with high turnover frequency (kcat = 1.03 × 102 h-1) for the conversion of the model substrate 3,5-di-tertbutylcatechol (3,5-DTBC) to 3,5-di-tertbutylquinone (3,5-DTBQ). Furthermore, molecular docking studies revealed that complex 1 was successfully localized inside the binding pocket of protein kinase (Akt), which validate the mechanism and mode of interaction of 1 that displayed cytotoxic activity experimentally. The obtained outcomes reveal that the complex 1 could be utilized as an encouraging perspective in the development of new therapeutic candidate for colon cancer.



中文翻译:

通过激活铜 (II) 复合物与 2-(quinolin-8-yloxy)(methyl)benzonitrile 和 8-hydroxyquinoline 偶联的线粒体途径评估人结直肠癌细胞系中的邻苯二酚酶模拟活性和细胞凋亡

为了评估基于金属的化疗候选药物对结直肠癌的细胞毒性潜力,我们合成了一种新的铜 (II) 络合物 [Cu(qmbn)(q)(Cl)] ( 1 )(其中,qmbn = 2-(quinolin -8-yloxy)(methyl)benzonitrile and q = 8-hydroxyquinoline) 并通过单晶 X 射线、粉末 XRD、FTIR 和热重分析 (TGA) 进行结构表征。结构分析表明,铜(II)离子以扭曲的四方锥体(τ = ∼0.1)存在,赤道位置连接了一个氯离子、氧原子和两个氮原子,顶端位置连接了一个氧原子。复合物1对人结直肠细胞系 (HCT116)的细胞毒性潜力表明,1通过激活 Bax(促凋亡蛋白)caspases-3 和 9 蛋白,诱导线粒体介导的细胞凋亡。有趣的是,发现配合物1是一个很好的电子转移催化剂候选者,它模拟具有高转换频率(k cat = 1.03 × 10 2 h -1)的邻苯二酚酶,用于转化模型底物 3,5-二叔丁基邻苯二酚( 3,5-DTBC) 到 3,5-二叔丁基醌 (3,5-DTBQ)。此外,分子对接研究表明,复合物1成功定位于蛋白激酶 (Akt) 的结合口袋内,验证了1相互作用的机制和模式。在实验中显示出细胞毒活性。获得的结果表明,复合物1可作为开发新的结肠癌候选药物的令人鼓舞的前景。

更新日期:2020-11-21
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