【作者】 刘霞；

【导师】 袁其朋； 邓炳华；

【作者基本信息】 北京化工大学 ， 化学工程与技术， 2018， 硕士

【摘要】 中国癌症死亡率高于全球平均水平17%,肿瘤治疗药物仍然存在靶标性差,毒副作用大的问题。随着研究者对分子生物学研究的不断深入,靶向型抗癌药物和天然抗癌药物因其毒副作用小而备受喜爱。其中靶向性药物中组蛋白去乙酰化酶抑制剂(HDACi)是目前研究的热点,而莱菔硫烷和莱菔素是目前人们发现的防癌和抗癌效果最好的天然产物之一,在进入体内后,它们的异硫氰酸酯基团会与含巯基的氨基酸反应变为稳定的氨基二硫代甲酸酯。有研究表明氨基二硫代甲酸酯基团具有广泛的生物活性,包括较好的肿瘤预防和抗肿瘤活性。所以,本课题首先设计合成出了不同类型的组蛋白去乙酰化酶抑制剂类化合物,包括羟肟酸类,邻苯二胺类和酰胺类三大类,希望筛、选出抑癌效果最佳的化合物类型。天然药物SFA和SFE的结构改造,.期待得到性质更加稳定,抗癌效果明显的抗癌药物。其次,通过癌细胞抑制实验,发现氨基二硫代甲酸酯类化合物中大多数化合物都比参比药物SFA和SFE显示出更高的抗癌活性,尤其对SMMC-7721癌细胞的抑制效果最佳,其中莱菔素衍生物R114,R115的IC50值为5.31和5.66(SFE的IC50为6.41)。莱菔硫烷衍生物W115,W120的IC50值为6.09和6.12(SFA的IC50为7.87)。进一步单克隆实验和细胞凋亡实验结果都证明R114和R115和W120对人肝癌细胞SMMC-7721的转移和扩散都有着很好的抑制效果。细胞周期实验结果表明R114,R115和W120将癌细胞SMMC-7721抑制在G2/M期,W115抑制在G0/G1期。其中R114和W115是本课题筛选出的针对抑制SMMC-7721癌细胞最具潜力的药物。更多还原

【Abstract】 The cancer mortality rate in china is 17%higher than that of the global average.Chemotherapeutic drugs still have poor target and toxic side effects.With the development of molecular biology,targeted anticancer drugs,natural anticancer drugs have been favored by researchers because of their low toxicity and side effects.Targeted drugs,such as histone deacetylase inhibitors(HDACi)are currently the focus of research,and SFA and SFE have become currently recognized as,among them,the best natural anti-cancer products.Once the SFA has enter the body,their isothiocyanate groups react with the thiol-containing amino acids to more stable aminodithioformates.Studies have shown that aminodithiocarbamate compounds have a wide range of biological activities,and considerable studies have found that amino-dithio compounds have better tumor prevention and anti-tumor activity.Firstly,the preseat work is focused on the design and synthesis of such histone deacetylase inhibitor compounds,including hydroxamic acids,benzamides and amides,and the structural modification of natural drugs SFA and SFE.The rationale behind this work is the expection that we could synthesize more stable and more effective anti-tumor drugs.Secondly,an in-vitro preliminary inhibition of cancer cell proliferation was performed on all synthesized compounds.The results showed that most compounds of aminodithiocarbamates have good inhibitory effects on cancer cells.R114 and R115 exhibited remarkable antiproliferative activity against SMMC-7721 with IC50 values of 5.31 μM and 5.66μM,compared to SFE whose IC50 was 6.41μM.W115 and W120 exhibited remarkable antiproliferative activity against SMMC-7721 with IC50 values are 6.09μM and 6.12μM(IC50 of SFA is 7.87μM).Further investigation of colony formation and apoptosis of human hepatocellular carcinoma cell line SMMC-7721 showed that R114,R115 and W120 had a good inhibitory effect on cancer metastasis and proliferation.We also found that R114,R115 and W120 possessed potent induction for SMMC-7721 cancer cell cycle arrest at G2/M phase,and W115 arrest at G0/G1 phase.This study indicated clearly that R114 and W115 were the most promising drugs for the inhibition of SMMC-7721 cancer cells of all synthetic compounds.更多还原