Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents
Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents
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DOI：
10.1016/j.ejmech.2019.05.015
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发表时间：
2019-08-15
影响因子：
6.7
通讯作者：
Abdel-Aziz, Mohamed
中科院分区：
文献类型：
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作者：
Hisham, Mohamed;Youssif, Bahaa G. M.;Abdel-Aziz, Mohamed
设计并合成了一系列含1，3，8-三取代或1，8-二取代黄嘌呤衍生物的新型黄嘌呤/NO供体杂化物。使用人乳腺上皮细胞系（MCF-10A）在细胞活力测定中测试合成的化合物，其中所有化合物在50 μ M的浓度下均表现出无细胞毒性作用和超过90%的细胞活力。含肟的化合物7a-b和17-24作为抗增殖剂比它们的非肟同系物6a-b和9-16更有活性。羟基亚氨基-苯乙基骨架化合物17-24比羟基亚氨基-乙基苯基乙酰胺7a-b衍生物更有活性。化合物18-20和22-24表现出EGFR抑制作用，IC 50范围为0.32 - 2.88 μ M。与作为参考药物的阿霉素相比，化合物18-20和22-24使Panc-1细胞系中的对照细胞的活性半胱天冬酶3的水平增加4-8倍。化合物18、22和23是最强的caspase-3诱导剂。化合物22和23增加了半胱天冬酶-8和9的水平，表明内源性和外源性途径的激活，并显示出在Panc-1人胰腺癌细胞中对Bax的有效诱导、Bcl-2蛋白水平的下调和细胞色素c水平的过表达。在Panc-1细胞系的细胞周期分析中，化合物23主要表现出在Pre-G1和G2/M期的细胞周期阻滞。预测化合物18-20和22-24的药物相似性曲线具有良好至优异的药物相似性曲线，特别是化合物18-20和23。最后在EGFR活性位点进行分子对接研究，推测其可能的结合模式。羟基亚氨基-苯乙基支架化合物17-24代表了优化其药代动力学和药效学特征的一个有趣的起点。(C)2019 Elsevier Masson SAS。All rights reserved.
A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 mu M. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 mu M. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles. (C) 2019 Elsevier Masson SAS. All rights reserved.