Nonhematotoxic naphthalene diimide modified by polyamine: synthesis and biological evaluation.
Nonhematotoxic naphthalene diimide modified by polyamine: synthesis and biological evaluation.
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DOI：
10.1021/jm300168w
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发表时间：
2012-03
影响因子：
7.3
通讯作者：
Yuxia Wang;Xing-Long Zhang;Jin Zhao;Songqiang Xie;Chaojie Wang
中科院分区：
文献类型：
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作者：
Yuxia Wang;Xing-Long Zhang;Jin Zhao;Songqiang Xie;Chaojie Wang
以提高抗肿瘤疗效和降低不良反应为目的，设计了3种芳香亚胺和二亚胺与不同的多胺偶联。体外实验结果表明，两种萘二亚胺-多胺偶联物对多种肿瘤细胞系的生长抑制作用强于氨酰胺。在初步的机制研究中，最有效的化合物9f被证实通过ROS介导的线粒体途径有效地诱导细胞凋亡。三种H22肿瘤移植模型的体内综合试验表明，9f在抑制作用和延长寿命方面改善了各项指标，降低了血液毒性，这是氨硝酸钠的主要缺点之一。更重要的是，我们观察到9f预防肺癌转移的能力明显提高，这增加了9f作为一种有前景的先导化合物的价值。这项工作支持了多胺的多功能性可能赋予母体药物一些有趣的生物学特性。
With the aim of up-regulating antitumor efficacy and down-regulating adverse effects, three types of aromatic imide and diimides were designed to couple with different polyamines. The in vitro assays revealed that two naphthalene diimide-polyamine conjugates could inhibit the growth of multiple cancer cell lines more potently than amonafide. 9f, the most potent compound, was verified to efficiently induce apoptosis via a ROS mediated mitochondrial pathway in a preliminary mechanistic study. The comprehensive in vivo trials on three H22 tumor transplant models demonstrated that 9f improved the indexes in terms of inhibitive effect and lifespan extension and reduced the hematotoxicity which is one of main drawbacks of amonafide. More importantly, the obviously elevated ability in preventing lung cancer metastasis was observed, which increased the value of 9f as a promising lead compound. This work supported that the versatile function of polyamines may endow some intriguing biological features to the parent drugs.