Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[c] acridine derivatives as new c-KIT promoter G-quadruplex binding ligands
Synthesis and evaluation of 7-substituted-5,6-dihydrobenzo[c] acridine derivatives as new c-KIT promoter G-quadruplex binding ligands
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7-取代-5,6-二氢苯并[c]吖啶衍生物作为新型c-KIT启动子G-四联体结合配体的合成和评价
DOI：
10.1016/j.ejmech.2017.02.051
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发表时间：
2017-04-21
影响因子：
6.7
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Guo, Qian-Liang;Su, Hua-Fei;Huang, Zhi-Shu
已有研究表明，用c-kit G-四链结合配体处理癌细胞可以降低其c-kit的表达水平，从而抑制细胞增殖，诱导细胞凋亡。本论文设计合成了一系列新的7-取代-5，6-二氢苯并[c]吖啶类化合物。随后的生物物理评价表明，这些衍生物能够有效地结合并稳定cKit G-四链，对双链DNA具有良好的选择性。结果发现，在5，6-二氢苯并[c]吖啶环的12位引入正电荷的12-N-甲基化衍生物与未甲基化的衍生物相比，对c-kit G-四链体DNA的结合亲和力相似，但稳定能力较低。进一步的分子模拟研究表明G-四链体与配体可能的结合方式。RT-PCR和Western印迹分析表明，化合物2b抑制了K562细胞中c-kit基因的转录和翻译，这与c-kit癌基因启动子作为有效的G-四链结合配体的性质一致。进一步的生物学评价表明，化合物2b可通过激活caspase-3级联通路诱导细胞凋亡。(C)2017年爱思唯尔·马森公司。版权所有。
It has been shown that treatment of cancer cells with c-KIT G-quadruplex binding ligands can reduce their c-KIT expression levels thus inhibiting cell proliferation and inducing cell apoptosis. Herein, a series of new 7-substituted-5,6-dihydrobenzo[c] acridine derivatives were designed and synthesized. Subsequent biophysical evaluation demonstrated that the derivatives could effectively bind to and stabilize cKIT G-quadruplex with good selectivity against duplex DNA. It was found that 12-N-methylated derivatives with a positive charge introduced at 12-position of 5,6-dihydrobenzo[c] acridine ring had similar binding affinity but lower stabilizing ability to c-KIT G-quadruplex DNA, compared with those of nonmethylated derivatives. Further molecular modeling studies showed possible binding modes of G-quadruplex with the ligands. RT-PCR assay and Western blot showed that compound 2b suppressed transcription and translation of c-KIT gene in K562 cells, which was consistent with the property of an effective G-quadruplex binding ligand targeting c-KIT oncogene promoter. Further biological evaluation showed that compound 2b could induce apoptosis through activation of the caspase-3 cascade pathway. (C) 2017 Elsevier Masson SAS. All rights reserved.