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Design, efficient synthesis, docking studies, and anticancer evaluation of new quinoxalines as potential intercalative Topo II inhibitors and apoptosis inducers.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-09-02 , DOI: 10.1016/j.bioorg.2020.104255
Eslam M Abbass 1 , Ali Kh Khalil 1 , Mohamed M Mohamed 1 , Ibrahim H Eissa 2 , Abeer M El-Naggar 1
Affiliation  

As an extension for our earlier effort in the field of discovery of anticancer agents acting on DNA and Topo II, eighteen quinoxaline derivatives were designed and synthesized. Such members were designed to possess the main essential pharmacophoric features of DNA intercalators. The cytotoxic potential of the synthesized compounds was assessed against a group of human cancer cell lines (HCT-116, HepG2, and MCF-7). Doxorubicin as potential intercalative Topo II inhibitor, was used as a positive reference. In general, compounds 12, 15, 19, 21, and 22 showed promising anti-proliferative activities against the three cell lines with IC50 values ranging from 2.81 to 10.23 µM. The cytotoxicities of the most active compounds against normal human cells (WI-38) were evaluated, and the results revealed that these compounds have low toxicity. Further examination for the most active anti-proliferative members as Topo II inhibitors was also performed, showing a narrow range of the inhibitory activities (from 0.45 to 1.06 µM). In addition, DNA/methyl green assay was carried out to evaluate DNA-binding potential of such compounds. The results indicated that these compounds have strong to moderate DNA-binding affinities ranging from 33.48 to 51.23 µM. Further studies exhibited the capability of compound 22 to induce apoptosis in HepG2 cells and can arrest growth of such cells at G2/M phase. Also, compound 22 produced a significant increase in the level of caspase- 3 (10 folds) and caspase-9 (7 folds) compared to the control cells. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the DNA-Topo II complex.



中文翻译:

设计,有效的合成,对接研究和新的喹喔啉类药物作为潜在的插入式Topo II抑制剂和凋亡诱导剂的抗癌评估。

作为我们在发现作用于DNA和Topo II的抗癌药领域的早期工作的扩展,设计和合成了18种喹喔啉衍生物。设计此类成员具有DNA嵌入剂的主要基本药效学特征。针对一组人类癌细胞系(HCT-116,HepG2和MCF-7)评估了合成化合物的细胞毒性潜力。阿霉素作为潜在的插入式Topo II抑制剂,被用作阳性参考。一般情况下,化合物12151921,和22显示出有希望的抗增殖活性针对与IC三种细胞系50值范围从2.81到10.23 µM。评估了活性最高的化合物对正常人细胞(WI-38)的细胞毒性,结果表明这些化合物具有较低的毒性。还对作为Topo II抑制剂的最具活性的抗增殖成员进行了进一步检查,发现抑制活性范围很窄(0.45至1.06 µM)。另外,进行了DNA /甲基绿测定以评估此类化合物的DNA结合潜力。结果表明这些化合物具有强至中等的DNA结合亲和力,范围为33.48至51.23 µM。进一步的研究显示了化合物22诱导HepG2细胞凋亡的能力,并可以阻止此类细胞在G2 / M期生长。另外,化合物22与对照细胞相比,Caspase-3产生的caspase-3(10倍)和caspase-9(7倍)水平显着增加。还进行了分子对接研究,以研究目标化合物与DNA-Topo II复合物之间可能的结合相互作用。

更新日期:2020-09-12
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