摘要
背景:芪类、1,2-二苯基衍生物(包括白藜芦醇和康布他汀)具有抗癌特性,特别是抗肿瘤血管生成。蟾酥素,CA-4,结合卡铂,已经到了甲状腺癌抑制剂的临床试验的最后阶段。这些化合物的作用方式包括通过干扰微管蛋白(DE)聚合来抑制血管生成。 目的:我们在Z构型中合成了五个E- 2-羟基二苯乙烯类化合物和七个二苯并[b,f]氧杂环庚三烯,其中甲基或硝基在不同的位置。本工作的目的是评估抗癌活性和分子机制以及这些化合物的作用。 结果:用四个新合成的二苯乙烯类化合物和七个氧合酶处理两个健康的EUFA30和HEK293,以及两个癌症的HeLa和U77细胞株。这两种化合物JJR5和JJR6对癌细胞的细胞毒作用最强,这两种被选择作进一步的研究。它们诱导细胞凋亡与亚G1或S细胞周期阻滞和PARP切割有关,而与半胱氨酸天冬氨酸蛋白酶3和7无关。蛋白质组差异分析的芪类细胞导致鉴定几乎涉及细胞周期管理,细胞凋亡,DNA修复和应激反应,如氧化应激的蛋白质。 结论:在新合成的二苯乙烯衍生物中,我们选择了两种有效的抗癌化合物,通过亚G1期细胞周期阻滞触发癌细胞晚期凋亡/坏死。它们改变细胞周期蛋白的表达,诱导DNA修复机制,通过酶参与细胞凋亡和氧化应激反应。化合物JJR5和JJR6可能是结构修饰(S)以获得活性更强的衍生物的基础。
关键词: 抗癌药物,二苯乙烯,氧杂环庚三烯,凋亡,细胞周期停止,EUFA 30,HEK 293,HeLa,U87。
Current Cancer Drug Targets
Title:Evaluation of Anti-cancer Activity of Stilbene and Methoxydibenzo[b,f] oxepin Derivatives
Volume: 18 Issue: 7
关键词: 抗癌药物,二苯乙烯,氧杂环庚三烯,凋亡,细胞周期停止,EUFA 30,HEK 293,HeLa,U87。
摘要: Background: Stilbenes, 1,2-diphenylethen derivatives, including resveratrol and combretastatins, show anticancer features especially against tumor angiogenesis. Fosbretabulin, CA-4, in combination with carboplatin, is in the last stages of clinical tests as an inhibitor of thyroid cancer. The mode of action of these compounds involves suppression of angiogenesis through interfering with tubulin (de)polymerization.
Objective: We have previously synthesized five E-2-hydroxystilbenes and seven dibenzo [b,f]oxepins in Z configuration, with methyl or nitro groups at varied positions. The aim of the present work was to evaluate the anticancer activity and molecular mechanism(s) of action of these compounds.
Results: Two healthy, EUFA30 and HEK293, and two cancerous, HeLa and U87, cell lines were treated with four newly synthetized stilbenes and seven oxepins. Two of these compounds, JJR5 and JJR6, showed the strongest cytotoxic effect against cancerous cells tested and these two were selected for further investigations. They induced apoptosis with sub-G1 or S cell cycle arrest and PARP cleavage, with no visible activation of caspases 3 and 7. Proteomic differential analysis of stilbene-treated cells led to the identification of proteins involved almost exclusively in cell cycle management, apoptosis, DNA repair and stress response, e.g. oxidative stress.
Conclusion: Among the newly synthesized stilbene derivatives, we selected two as potent anticancer compounds triggering late apoptosis/necrosis in cancerous cells through sub-G1 phase cell cycle arrest. They changed cyclin expression, induced DNA repair mechanisms, enzymes involved in apoptosis and oxidative stress response. Compounds JJR5 and JJR6 can be a base for structure modification(s) to obtain even more active derivatives.
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Cite this article as:
Evaluation of Anti-cancer Activity of Stilbene and Methoxydibenzo[b,f] oxepin Derivatives, Current Cancer Drug Targets 2018; 18 (7) . https://dx.doi.org/10.2174/1568009617666170623120742
DOI https://dx.doi.org/10.2174/1568009617666170623120742 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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