Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of lim...Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.展开更多
目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁...目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁共振碳谱(nuclear magnetic resonance carbon spectrum,^(13)C-NMR)和高分辨质谱(high resolution mass spectrometry,HRMS)对衍生物的结构进行确认;用HepG2、A549和HCT-116肿瘤细胞系和L02肝正常细胞系对衍生物的抗肿瘤活性和细胞毒选择性进行评价;用4’,6-二脒基-2-苯基吲哚(4,6-diamidino-2-phenylindole,DAPI)、吉姆萨(Giemsa)染色和流式细胞术分析优势衍生物对细胞凋亡的影响;用细胞划痕实验和鹌鹑胚绒毛尿囊膜(quail chick chorioallantoic membrane,qCAM)模型评价衍生物对细胞迁移和血管生成的影响。结果衍生物AL-8对肝癌细胞HepG2表现出较好的增殖抑制活性[IC_(50)=(1.53±0.39)μmol·L^(-1)],其活性优于前体药物利尼伐尼[IC_(50)=(4.93±0.62)μmol·L^(-1)]和紫草素[IC_(50)=(1.91±0.17)μmol·L^(-1)],而对肝正常细胞系L02的毒性较小。作用机制研究结果表明,其能显著诱导肿瘤细胞凋亡,抑制肿瘤细胞迁移和血管新生。结论筛选得到高效、低毒的衍生物AL-8,为紫草素-利尼伐尼抗肿瘤衍生物的发现提供参考。展开更多
基金the National Nature Science Foundation of China,Nos.30770971,30800518,81070362,81172470 and 81372629two key projects from the Nature Science Foundation of Hunan Province,Nos.11JJ2049 and 12JJ3118
文摘Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.
文摘目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁共振碳谱(nuclear magnetic resonance carbon spectrum,^(13)C-NMR)和高分辨质谱(high resolution mass spectrometry,HRMS)对衍生物的结构进行确认;用HepG2、A549和HCT-116肿瘤细胞系和L02肝正常细胞系对衍生物的抗肿瘤活性和细胞毒选择性进行评价;用4’,6-二脒基-2-苯基吲哚(4,6-diamidino-2-phenylindole,DAPI)、吉姆萨(Giemsa)染色和流式细胞术分析优势衍生物对细胞凋亡的影响;用细胞划痕实验和鹌鹑胚绒毛尿囊膜(quail chick chorioallantoic membrane,qCAM)模型评价衍生物对细胞迁移和血管生成的影响。结果衍生物AL-8对肝癌细胞HepG2表现出较好的增殖抑制活性[IC_(50)=(1.53±0.39)μmol·L^(-1)],其活性优于前体药物利尼伐尼[IC_(50)=(4.93±0.62)μmol·L^(-1)]和紫草素[IC_(50)=(1.91±0.17)μmol·L^(-1)],而对肝正常细胞系L02的毒性较小。作用机制研究结果表明,其能显著诱导肿瘤细胞凋亡,抑制肿瘤细胞迁移和血管新生。结论筛选得到高效、低毒的衍生物AL-8,为紫草素-利尼伐尼抗肿瘤衍生物的发现提供参考。
