XJIPC OpenIR  > 资源化学研究室
Thesis Advisor李晓波
Degree Grantor中国科学院研究生院
Place of Conferral北京
Degree Discipline有机化学
Keyword二硫代甲酸酯类化合物 抗肿瘤 抗乙肝病毒 实时定量pcr Hepg2.2.15 细胞
Abstract实验室前期以L-苯丙氨酸、L-丙氨酸、L-亮氨酸、L-异亮氨酸、L-谷氨酸及L-甘氨酸甲酯为原料,通过碱催化,与CS2和卤代烷缩合反应,合成18种氨基酸酯基二硫代甲酸酯类化合物(HE1-18)。化合物的结构及组成经过质谱、1H NMR和熔点仪测试技术进行了表征。 本研究对18种化合物进行了体外抗肿瘤及抗病毒活性筛选,并进行了分子机理研究。结果如下: 1)利用MTT法测定目标化合物HE1-18对子宫颈癌HeLa,肝癌HepG2,胃癌BGC-823,乳腺癌MCF-7,结肠癌SW-480细胞株的增殖抑制作用,结果表明化合物HE-5, 6, 11, 12, 17和18可抑制肿瘤细胞的增殖。 2)选取上述6种能够抑制肿瘤细胞增殖的化合物(HE-5, 6, 11, 12, 17和18),处理人子宫颈癌细胞HeLa和SiHa细胞,通过流式细胞术和Western blotting测定其诱导细胞凋亡的能力。结果显示化合物HE-11,12,17和18可诱导子宫颈癌细胞发生凋亡,为P53依赖的内源性细胞凋亡途径。 3)同样选取上述6种能够抑制肿瘤细胞增殖的化合物处理人子宫颈癌相关肿瘤细胞系HeLa细胞 (HPV18阳性) 和SiHa 细胞 (HPV16 阳性),然后采用实时荧光定量PCR检测其E6 和E7基因mRNA的相对表达量,结果表明化合物HE-17和HE-18能够在体外抑制HPV E6基因mRNA 的表达。 4)以HepG2.2.15细胞为筛选模型,采用ELISA法测定目标化合物对HBsAg和HBeAg的抑制效果;实时荧光定量PCR法检测上清液中HBV DNA的相对表达量。结果表明相对于阳性对照拉米呋啶,化合物HE-14和15能够较好的抑制HBV抗原分泌和病毒DNA的复制。 结论:HE-14和15具有较好的抗乙肝病毒活性,HE-17和18具有较好的抗子宫颈癌及抗-HPV活性。
Other AbstractA series of dithiocarbamates derivatives (compounds 1-18) were previously in the laboratory synthesized using base catalysis and aldol reaction between alkyl halide and carbon bisulfide on the basis of methyl ester of L-phenylalanine, L-alanine, L-leucine, L-isoleucine, L-glutamic acid, and L-glycine, and their characters were elucidated by MS, 1 H-NMR and Melting Point. The novel dithiocarbamates derivatives were evaluated for their activities of anti-cancer and anti-virus, and their mechanisms in vitro. Firstly, Cell proliferation of each compounds were determined by MTT assay in five human cancer cell lines: cervical (HeLa), hepatocellular (HepG2), gastric (BGC-823), breast (MCF-7) and colon (SW480), which showed that compounds (5, 6, 11, 12, 17, and 18) were the most active option with the inhibited cell proliferation. Secondly, the effects of apoptosis were investigated by a flow cytometry and western bolting in human cervical cancer lines (HeLa and SiHa), which indicated that compounds (11, 12, 17, and 18) induced apoptosis through p53-mediated intrinsic pathway in human cervical cell lines (HeLa and SiHa). Thirdly, relative gene expression of E6 and E7 mRNA of HPV18/16 were evaluated by real-time quantitative PCR in human cervical cancer cell lines, HeLa cell (HPV18 positive) and SiHa cell (HPV16 positive); these results demonstrated that compounds (17 and 18) exhibited the decreased expression of E6 oncogene of HPV type16 and type18. In addition, all of compounds were evaluated for their anti-hepatitis B virus activities and cytotoxicities in HepG2.2.15 cells, which demonstrated that compounds (14 and 15) exhibited the inhibition of hepatitis B virus antigen secretion and DNA replication than lamivudine as a positive control. Colclusion: Compounds (14 and 15) were the most active option with the anti-HBV; and compounds (17 and 18) were the most active option with the cervical cancer and HPV.
Document Type学位论文
Recommended Citation
GB/T 7714
祁红学. 二硫代甲酸酯衍生物抗病毒、抗肿瘤活性的评价及其分子机制研究[D]. 北京. 中国科学院研究生院,2012.
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