4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies
4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies
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4-甲基伞形酮类似物作为抗癌剂：合成和细胞药理学研究
DOI：
10.2174/1871520616666160926113109
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发表时间：
2017-01-01
影响因子：
2.8
通讯作者：
Wang, Heng-Shan
中科院分区：
文献类型：
--
作者：
Huang, Ri-Zhen;Hua, Shi-Xian;Wang, Heng-Shan
背景资料：癌症是世界范围内最严重的临床问题之一，并且已经投入相当大的努力来发现具有新的作用模式的治疗剂。天然和人工合成的香豆素类化合物因其结构特征多样、生物活性显著而引起人们的广泛关注，目的：合成一系列含脲基哌嗪和硫脲基哌嗪的4-MU类化合物，并对其抗肿瘤活性进行评价，寻找有效的抗肿瘤药物。MTT法检测细胞增殖、凋亡、细胞周期、活性氧生成及细胞内钙离子浓度。免疫印迹法检测细胞凋亡和增殖相关蛋白的表达。结果：大部分目标化合物对受试癌细胞具有潜在的抗肿瘤活性，但对正常细胞的细胞毒性较低。化合物4l抑制NCI-H460细胞的生长和增殖，并导致细胞凋亡。在NCI-H460细胞中使用4l进行的连续研究表明，该化合物诱导细胞内活性氧簇产生和钙超载，抑制核因子-kappa B（NF-kappa B）活性并调节抗和促凋亡蛋白。此外，化合物41能有效地将NCI-H460细胞阻滞于G2期，并改变细胞周期调控蛋白，尤其是cyclin B1。结论：化合物41通过靶向细胞凋亡途径对NCI-H460细胞具有明显的体外抗肿瘤作用。这些结果表明，4-MU衍生物的合理设计策略可能会发现潜在的抗癌药物。
Background: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties.Objective: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs.Method: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis-and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR.Results: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-kappa B (NF-kappa B) activity and regulated anti-and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1.Conclusion: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.