四类天然产物及其衍生物的抗氧化和抗肿瘤活性研究
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摘要
为从天然产物中寻找有效的抗氧化剂用于预防和治疗与自由基相关疾病及寻找安全有效的抗肿瘤先导化合物,本论文研究了四类天然产物及其衍生物的抗氧化和抗肿瘤活性。
我们采用不同的体外抗氧化模型,包括清除超氧阴离子和1,1-二苯基苦基苯肼(DPPH)自由基,抑制大鼠肝(脑)匀浆脂质过氧化,螯合金属亚铁离子,抑制过氧化氢(H_2O_2)诱导质粒超螺旋DNA断裂及大鼠肾上腺嗜铬瘤细胞(PC12)的损伤,来研究水飞蓟宾类衍生物(化合物1.1-1.22)、新木脂素类衍生物(化合物2.1-2.14)及生姜中二苯庚烷类化合物(化合物3.1-3.5)的体外抗氧化活性。
此外,我们用MTT法检测了化合物3.1-3.5及黑紫橐吾中含氯艾里莫芬烷型倍半萜化合物(化合物4.1)的体外细胞毒活性,并以人慢性髓源性白血病细胞(K562)为研究对象,研究化合物4.1可能的抗肿瘤机制。用倒置显微镜观察化合物4.1对K562细胞形态学的影响;JC-1、吖啶橙(AO)和溴乙啶(EB)荧光染色法检测化合物4.1对K562细胞的凋亡作用;Western blot法检测细胞凋亡相关蛋白ERK1/2,JNK,Bcl-2和Bax及细胞周期相关蛋白CDK2和CDK4的表达变化;流式细胞术定量分析凋亡现象和细胞周期分布变化。
体外抗氧化结果表明:①水飞蓟宾类衍生物具有不同的抗氧化活性,构效关系研究表明,化合物E环酚羟基邻位有烷氧基取代有利于提高化合物1.1-1.8的抗氧化活性;取代基电子云密度对化合物1.9-1.22的抗氧化活性有较大影响。②新木脂素类衍生物2.4和2.13具有显著的抗氧化活性。③化合物3.1-3.5具有显著的抗氧化活性,同时实验结果提示化合物3.1和3.3可能有潜在的促氧化作用。
体外MTT检测结果表明化合物3.3对K562和K562/ADR细胞生长都有抑制作用。化合物4.1对不同来源的肿瘤细胞株有不同程度的抑制作用,并且化合物4.1对阿霉素耐药株有浓度依赖性逆转作用。机制研究表明ERK1/2和JNK通路可能介导了化合物4.1诱导的K562细胞凋亡及G1期阻滞。本论文首次研究了化合物4.1的抗肿瘤活性及其可能的作用机制,为该化合物进一步开发为抗肿瘤药物提供了重要信息。
To find effective antioxidants from natural products to prevent or therapy diseases related to free radicals and to search safe and efficient lead compounds for cancer therapy. The antioxidant and anti-tumor properties of four kinds of natural products and their derivatives were investigated in this research.
Different in vitro antioxidant models, such as scavenging superoxide anion and 1,1-diphenyl-2- picrylhydrazyl (DPPH), inhibiting rat liver or brain homogenates lipid peroxidation, chelating ferrous ion (Fe~(2+)), as well as inhibiting the insult of the plasmid DNA and rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H_2O_2), were employed to evaluate the antioxidant activities of silybin derivatives (compounds 1.1-1.22), neolignan derivatives (compounds2.1-2.14), and diarylheptanoids isolated from Zingiber officinale (compounds 3.1-3.5).
Moreover, we also evaluated the in vitro cytotoxicity of compounds 3.1-3.5 and 4.1 (isolated from Ligularia atroviolacea) against human tumor cells by MTT assay. The possible antitumor mechanism of compound 4.1 was investigated in human chronic myelogenous leukemia (K562) cell line. The morphological change of K562 cells treated by compound 4.1 was observed on inverted microscope. Cell morphology of compound 4.1-induced apoptosis was investigated by staining the cells with JC-1 and a combination of the fluorescent DNA-binding dyes acridine orange (AO) and ethidium bromide (EB). Western blot analysis was used to examine the expression changes of apoptosis-related proteins, including ERK1/2, JNK, Bcl-2 and Bax, as well as the cell-cycle-related proteins, such as CDK2 and CDK4. The flow cytometry analysis was used to investigate the apoptosis and the changes of cell-cycle distribution.
The results of in vitro antioxidant assay are listed as follows. 1) Silybin derivatives possessed different antioxidant properties. The study of SARs indicated that the alkoxy moiety substituted on the ortho of phenolic hydroxyl group of E ring can increase the efficacy of compounds 1.1-1.8, and the electron density of the substitutents plays an important role on the antioxidative effects of compounds 1.9-1.22. 2) The data obtained from in vitro and cell models demonstrated that the neolignan derivatives 2.4 and 2.13 exhibited remarkable antioxidative and neuroprotective activities. 3) Compounds (3.1-3.5) showed significant antioxidant activities. However, the pro-oxidant activity of compounds 3.1 and 3.5 was also observed.
The MTT test revealed that compound 3.3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR).
The growth of different human cancer cell lines was inhibited by compound 4.1 in vitro assays and the drug resistance of K562/ADR was reversed after being treated with compound 4.1 in a dose-dependent manner. The study of its possible mechanisms exhibited that ERK1/2 and JNK pathway mediated the K562 cells apoptosis and G1 arrest induced by compound 4.1. This is the first time to report the antitumor activity and its possible mechanism of compound 4.1, and it might provide significant information for further exploring this compound as a novel antitumor agent.
我们采用不同的体外抗氧化模型,包括清除超氧阴离子和1,1-二苯基苦基苯肼(DPPH)自由基,抑制大鼠肝(脑)匀浆脂质过氧化,螯合金属亚铁离子,抑制过氧化氢(H_2O_2)诱导质粒超螺旋DNA断裂及大鼠肾上腺嗜铬瘤细胞(PC12)的损伤,来研究水飞蓟宾类衍生物(化合物1.1-1.22)、新木脂素类衍生物(化合物2.1-2.14)及生姜中二苯庚烷类化合物(化合物3.1-3.5)的体外抗氧化活性。
此外,我们用MTT法检测了化合物3.1-3.5及黑紫橐吾中含氯艾里莫芬烷型倍半萜化合物(化合物4.1)的体外细胞毒活性,并以人慢性髓源性白血病细胞(K562)为研究对象,研究化合物4.1可能的抗肿瘤机制。用倒置显微镜观察化合物4.1对K562细胞形态学的影响;JC-1、吖啶橙(AO)和溴乙啶(EB)荧光染色法检测化合物4.1对K562细胞的凋亡作用;Western blot法检测细胞凋亡相关蛋白ERK1/2,JNK,Bcl-2和Bax及细胞周期相关蛋白CDK2和CDK4的表达变化;流式细胞术定量分析凋亡现象和细胞周期分布变化。
体外抗氧化结果表明:①水飞蓟宾类衍生物具有不同的抗氧化活性,构效关系研究表明,化合物E环酚羟基邻位有烷氧基取代有利于提高化合物1.1-1.8的抗氧化活性;取代基电子云密度对化合物1.9-1.22的抗氧化活性有较大影响。②新木脂素类衍生物2.4和2.13具有显著的抗氧化活性。③化合物3.1-3.5具有显著的抗氧化活性,同时实验结果提示化合物3.1和3.3可能有潜在的促氧化作用。
体外MTT检测结果表明化合物3.3对K562和K562/ADR细胞生长都有抑制作用。化合物4.1对不同来源的肿瘤细胞株有不同程度的抑制作用,并且化合物4.1对阿霉素耐药株有浓度依赖性逆转作用。机制研究表明ERK1/2和JNK通路可能介导了化合物4.1诱导的K562细胞凋亡及G1期阻滞。本论文首次研究了化合物4.1的抗肿瘤活性及其可能的作用机制,为该化合物进一步开发为抗肿瘤药物提供了重要信息。
To find effective antioxidants from natural products to prevent or therapy diseases related to free radicals and to search safe and efficient lead compounds for cancer therapy. The antioxidant and anti-tumor properties of four kinds of natural products and their derivatives were investigated in this research.
Different in vitro antioxidant models, such as scavenging superoxide anion and 1,1-diphenyl-2- picrylhydrazyl (DPPH), inhibiting rat liver or brain homogenates lipid peroxidation, chelating ferrous ion (Fe~(2+)), as well as inhibiting the insult of the plasmid DNA and rat pheochromocytoma (PC12) cells induced by hydrogen peroxide (H_2O_2), were employed to evaluate the antioxidant activities of silybin derivatives (compounds 1.1-1.22), neolignan derivatives (compounds2.1-2.14), and diarylheptanoids isolated from Zingiber officinale (compounds 3.1-3.5).
Moreover, we also evaluated the in vitro cytotoxicity of compounds 3.1-3.5 and 4.1 (isolated from Ligularia atroviolacea) against human tumor cells by MTT assay. The possible antitumor mechanism of compound 4.1 was investigated in human chronic myelogenous leukemia (K562) cell line. The morphological change of K562 cells treated by compound 4.1 was observed on inverted microscope. Cell morphology of compound 4.1-induced apoptosis was investigated by staining the cells with JC-1 and a combination of the fluorescent DNA-binding dyes acridine orange (AO) and ethidium bromide (EB). Western blot analysis was used to examine the expression changes of apoptosis-related proteins, including ERK1/2, JNK, Bcl-2 and Bax, as well as the cell-cycle-related proteins, such as CDK2 and CDK4. The flow cytometry analysis was used to investigate the apoptosis and the changes of cell-cycle distribution.
The results of in vitro antioxidant assay are listed as follows. 1) Silybin derivatives possessed different antioxidant properties. The study of SARs indicated that the alkoxy moiety substituted on the ortho of phenolic hydroxyl group of E ring can increase the efficacy of compounds 1.1-1.8, and the electron density of the substitutents plays an important role on the antioxidative effects of compounds 1.9-1.22. 2) The data obtained from in vitro and cell models demonstrated that the neolignan derivatives 2.4 and 2.13 exhibited remarkable antioxidative and neuroprotective activities. 3) Compounds (3.1-3.5) showed significant antioxidant activities. However, the pro-oxidant activity of compounds 3.1 and 3.5 was also observed.
The MTT test revealed that compound 3.3 exhibited certain cytotoxicities against human chronic myelogenous leukemia cells (K562) and its adriamycin-resistant cells (K562/ADR).
The growth of different human cancer cell lines was inhibited by compound 4.1 in vitro assays and the drug resistance of K562/ADR was reversed after being treated with compound 4.1 in a dose-dependent manner. The study of its possible mechanisms exhibited that ERK1/2 and JNK pathway mediated the K562 cells apoptosis and G1 arrest induced by compound 4.1. This is the first time to report the antitumor activity and its possible mechanism of compound 4.1, and it might provide significant information for further exploring this compound as a novel antitumor agent.
引文
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