Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: Design, synthesis and DNA targeting-induced apoptosis.
Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: Design, synthesis and DNA targeting-induced apoptosis.
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DOI：
10.1016/j.ejmech.2019.02.072
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发表时间：
2019-05
影响因子：
6.7
通讯作者：
Jing-Mei Yuan;Kai Wei;Guo-Hai Zhang;Nan Chen;Xin Wei;Cheng-Xue Pan;Dong-Liang Mo;Gui-Fa Su
中科院分区：
文献类型：
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作者：
Jing-Mei Yuan;Kai Wei;Guo-Hai Zhang;Nan Chen;Xin Wei;Cheng-Xue Pan;Dong-Liang Mo;Gui-Fa Su
设计合成了30个隐甲酸乙酯和阿罗马西林类化合物。对四种人癌细胞系(HepG-2、T24、NCI-H460和MGC-803)和一种正常人细胞系(HL-7702)进行了细胞毒性评价。8-Fluoro-10-(N-3-dimethylaminopropyl)amino-11H-indeno[1，2-b]quinoline(5b)具有较强的抗癌活性，IC50值在0.31~11.97 μ之间，被认为是最有希望的候选化合物。分子机制研究表明，5b不仅能与G-四链体强烈结合，还能插入到超螺旋DNA中，导致DNA双链断裂。此外，5b使细胞周期停滞于S/G2期，并诱导细胞凋亡。经5b处理后，促凋亡蛋白Bak、Bax和Bim表达上调，抗凋亡蛋白Bcl2和Bclxl表达下调，效应蛋白caspase-3/9被激活启动细胞凋亡。最后在MGC-803移植瘤模型中验证了5B的抗癌活性，其肿瘤生长抑制率(TGI)高达53.2%，且无明显毒性。综上所述，这些结果表明5b可能是用于癌症治疗的细胞毒性抗肿瘤药物的潜在候选者。
Thirty Cryptolepine and Aromathecin based mimics were designed and synthesized. Their cytotoxicity was evaluated in four human cancer cell lines (HepG-2, T24, NCI-H460 and MGC-803) and one normal human cell line (HL-7702). Most compounds exhibited potent anticancer activity with IC50values from 0.31 to 11.97 μM. 8-Fluoro-10-(N-3-dimethylaminopropyl)amino-11H-indeno[1,2-b]quinoline (5b) was identified as the most promising candidate in view of its anticancer activity. Molecular mechanism studies suggested that5bnot only could strongly bind to G-quadruplex, but intercalate into supercoil DNA and resulted in significant DNA double-strand break as well. Furthermore,5bcaused cell cycle arrest at S/G2 phase and induced apoptosis. After treatment with5b, pro-apoptotic proteins Bak, Bax and Bim were up-regulated, anti-apoptotic proteins Bcl-2 and Bcl-xL were down-regulated, and the effector caspase-3/9 was activated to initiate apoptosis. The anticancer activity of5bwas finally validated in a MGC-803 xenograft tumor model with tumor growth inhibition (TGI) up to 53.2%, while displaying no obvious toxicity. Taken together, these results suggest that5bmay be a potential candidate of cytotoxic antineoplastic drugs for cancer therapy.