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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies
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Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies

机译：吖酮 - 嘧啶杂种 - 设计，合成，抗性癌细胞细胞的细胞毒性研究和分子对接研究

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Abstract Hybrid systems of acridones with substituted pyrimidines were designed with an objective of discovering next generation anticancer agents targeting multiple mechanisms in the cancer cell. Hybrid compounds were synthesized by simple and convenient methods in the lab, characterized by NMR and Mass spectral methods and screened for cytotoxicity against A549 (lung), Hela (cervical), MCF7 (breast) and MDA-MB-231 (breast) cancer cell lines respectively. Evaluation of compounds for cell proliferation identified active compounds 11b , 11d and 11h against MCF7, MDA-MB-231 and A549?cell lines. Further absorption titrations with CT-DNA and gel electrophoresis identified that hybrid molecules displayed anticancer activity partly by DNA intercalation. Also further results of western blotting assay with Akt kinase identified that hybrid compounds have the ability to inhibit the Akt kinase activity and induce apoptosis, with ABCC1 suggests that active compounds too have the ability to modulate multidrug resistance (MDR) associated with ABCC1/MRP1. Selective Akt1 kinase assay have identified 11a , 11b , 11d and 11h as potential inhibitors. Molecular docking studies identified the orientation and binding interactions at the active site of Akt1 and DNA. Compounds 12e and 12f have shown good cytotoxicity profile against lung cancer cell lines of sensitive and resistant type. Acute toxicity study of compound 12f at the dose of 5000?mg/kg has identified no signs of clinical toxicity. Prediction of ADMET properties and oral toxicity of the drug likeness features of new hybrid systems were carried out using software's. This experimental data suggests that hybrid systems of acridone with substituted pyrimidines can be taken as a lead for the design of efficient inhibitors and active compounds which can be taken up for further studies. Graphical abstract Display Omitted Highlights ? Hybrid molecules of acridone and substituted pyrimidines with carbohydrazide as a linker were designed and synthesized. ? Absorption titrations and Gel Electrophoresis study identified DNA intercalation ability of 11b and 11d . ? Compounds 11a , 11b , 11d and 11h have ability to reduce to expression of MRP1 and pAkt. ? Computational applications Qikprop and ProTox identified the drug likeness and toxicity features of hybrid molecules. ? Molecular docking studies were performed to study binding interactions at the active site of DNA and Akt.
机译：摘要设计具有取代嘧啶的吖啶的杂种系统，目的是发现靶向癌细胞中多种机制的下一代抗癌剂。通过实验室中的简单和方便的方法合成杂化化合物，其特征在于NMR和质谱方法，并筛选对A549（肺），HERA（宫颈），MCF7（乳房）和MDA-MB-231（乳房）癌细胞和MDA-MB-231（乳腺）癌细胞的细胞毒性分别线。对细胞增殖化合物的评价鉴定了对MCF7，MDA-MB-231和A549？细胞系的活性化合物11b，11d和11h。使用CT-DNA和凝胶电泳的进一步吸收滴定鉴定出杂化分子部分通过DNA嵌入部分显示抗癌活性。还通过AKT激酶鉴定蛋白质印迹测定的进一步结果确定，杂化化合物具有抑制AKT激酶活性并诱导细胞凋亡的能力，ABCC1表明活性化合物具有调节与ABCC1 / MRP1相关的多药耐药性（MDR）的能力。选择性AKT1激酶测定已鉴定为潜在抑制剂11A，11B，11D和11H。分子对接研究鉴定了AKT1和DNA活性位点的取向和结合相互作用。化合物12e和12f显示出良好的细胞毒性曲线对肺癌细胞系的敏感和抗性型。化合物12f剂量为5000Ω·mg / kg的急性毒性研究已鉴定出临床毒性的迹象。使用软件进行了新的混合系统的吸毒者特征的探测性能和口服毒性的预测。该实验数据表明，具有取代嘧啶的吖啶酮的混合系统可以作为设计有效抑制剂和活性化合物的铅，其可用于进一步研究。图形抽象显示省略了亮点？设计并合成了吖啶酮的杂化分子和具有碳水化合物作为接头的嘧啶的嘧啶。还是吸收滴定和凝胶电泳研究确定了11B和11D的DNA嵌入能力。还是化合物11a，11b，11d和11h具有减少MRP1和PAKT的表达的能力。还是计算应用QikProp和Protox确定了杂化分子的药物似的特征。还是进行分子对接研究以研究DNA和Akt活性位点的结合相互作用。

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