Design, Synthesis, and Biological Evaluation of Mitochondria Targeted Flavone-Naphthalimide- Polyamine Conjugates with Antimetastatic Activity
Design, Synthesis, and Biological Evaluation of Mitochondria Targeted Flavone-Naphthalimide- Polyamine Conjugates with Antimetastatic Activity
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DOI：
10.1021/acs.jmedchem.6b01846
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发表时间：
2017-03-09
影响因子：
7.3
通讯作者：
Wang, Chaojie
中科院分区：
文献类型：
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作者：
Dai, Fujun;Li, Qian;Wang, Chaojie
大约90%的癌症相关死亡是由播散性肿瘤引起的，这表明目前的治疗无效，迫切需要抗转移药物。采用基于片段的药物设计方法，构建了一个含有黄酮和萘酰亚胺基团的新型药效团，并合成了一系列8个黄酮萘酰亚胺多胺缀合物。体外评价显示，具有homospermidine基序的化合物6c在癌细胞和正常肝细胞之间显示出比amonafide更好的细胞选择性。在两个肝细胞癌（HCC）模型的体内试验证实，6c有效地抑制肺转移与改善的器官指数相比，氨萘非。各种实验表明，6c作为一种潜在的荧光化学探针可以靶向线粒体。对6c作用机制的初步研究表明，它可能利用多胺转运蛋白进入细胞，定位于线粒体，选择性地导致活性氧（ROS）在肝癌细胞而不是正常肝细胞中过量产生，并最终通过多种ROS介导的信号通路导致肝癌细胞凋亡和迁移抑制。
Approximately 90% of cancer-associated deaths result from disseminated tumors, indicating the ineffectiveness of current therapies and the imperative need of antimetastatic drugs. A novel pharmacophore with flavonoid and naphthalimide moieties was constructed, by using a fragment-based drug design and a series of eight flavone naphthalimide polyamine conjugates were synthesized. In vitro evaluation revealed that compound 6c with a homospermidine motif displayed better cell selectivity between cancerous and normal liver cells than amonafide did. The in vivo assays on two hepatocellular carcinoma (HCC) models verified that 6c potently suppressed pulmonary metastasis with improved organ indexes compared to amonafide. Various experiments showed that 6c as a potential fluorescent chemical probe could target the mitochondria. Preliminary investigation into the mechanism of action Of 6c indicated that it might harness a polyamine transporter for cell entrance, localize in the mitochondria, selectively cause reactive oxygen species (ROS) overproduction in hepatoma cells instead of normal liver cells, and finally lead to HCC cell apoptosis and migration inhibition via multiple ROS-mediated signaling pathways.