多胺修饰的萘酰亚胺合成及抗肿瘤活性评价

发布时间：2018-05-25 11:01

本文选题：1 + 8萘酰亚胺　；参考：《河南大学》2014年硕士论文

【摘要】：近些年来多胺修饰的多胺缀合物在抗癌试剂方面的应用引起了人们的广泛关注,研究表明：天然或合成多胺有潜力发展成为一种有效利用细胞膜上多胺转运体(PAT)的靶向载体,它们可能具备提高化合物细胞选择性和生物活性的能力。萘酰亚胺类化合物作为抗癌类药物研究方面,已经发现一些经典化合物,如氨萘非特(amonafide)和米托萘胺(nitonafide),其中氨萘非特已处于Ⅲ期临床试验。但在临床试验中发现其一些不足之处,如具有神经毒性、骨髓抑制及对不同肿瘤表现出差异性等。大量实验发现萘酰亚胺类化合物在抗肿瘤方面,表现出较强的抑制作用,同时在抑制肿瘤转移方面也有较好作用,对萘酰亚胺类衍生物结构修饰目的是增效及减少毒性等不良反应,增加该类化合物对肿瘤细胞的靶向作用。本文就基于多胺是靶向运药载体,增加药物的靶向选择性出发,主要完成以下几点工作： (1)阐述当前多胺及萘酰亚胺类衍生物在药学上所具有的现实意义及近期研究的新进展。 (2)通过对Amonafide氨基和4-溴-1,8萘二甲酸酐的修饰,设计合成了2个系列的线性多胺缀合物并通过“连接臂”结构变化对其抗肿瘤活性作出测试,从中筛选出生物活性较好的先导化合物。本文合成了2个系列共11个目标化合物,第一个系列有9个丙酰化萘酰亚胺类衍生物,第二个系列为2个多胺手臂的多胺缀合物。这11个化合物都是新化合物,且结构均经过核磁、质谱和元素分析确认；此外通过MTT法测试目标化合物对HepG2(肝癌细胞)抑制的生物活性。结果表明目标化合物中部分药物的体外抗肿瘤活性明显优于氨萘菲特(Amonafide),并且其中化合物7c,7d,7e,11i,11j对HepG2(肝癌细胞)具有良好的抑制作用。
[Abstract]:In recent years, the application of polyamine-modified polyamine conjugates in anticancer reagents has attracted widespread attention. Studies have shown that natural or synthetic polyamines have the potential to develop into a target carrier for the effective use of polyamine transporter (PATs) on cell membranes. They may have the ability to improve cell selectivity and biological activity of compounds. In the research of naphthalimide compounds as anticancer drugs, some classical compounds, such as aminonaphthalene amonafide, and mitonaphthylamine nitonafidea have been found, among which amineferte has been in phase III clinical trials. In clinical trials, however, some shortcomings were found, such as neurotoxicity, bone marrow suppression, and differences in different tumors. A large number of experiments have found that naphthalimide compounds have a strong inhibitory effect on tumor and have a good effect in inhibiting tumor metastasis. The purpose of structural modification of naphthalimide derivatives is to enhance the toxicity and increase the targeting effect of these compounds on tumor cells. Based on the fact that polyamines are the carrier of targeted drug delivery and the targeting selectivity of drugs is increased, the main work of this paper is as follows: In this paper, the pharmacological significance of polyamines and naphthalimide derivatives and the recent progress in pharmaceutical research are reviewed. Two series of linear polyamine conjugates were designed and synthesized by modification of Amonafide amino groups and 4-bromo-1-butadiene-8-naphthalene dicarboxylic anhydride, and their antitumor activities were tested by structural changes in the "connecting arm". The leading compounds with good biological activity were screened out. In this paper, two series of 11 target compounds have been synthesized. The first series has 9 malonyl naphthalimide derivatives, and the second series is two polyamine conjugates with two polyamines. The 11 compounds were all new compounds, and their structures were confirmed by NMR, MS and elemental analysis. In addition, the bioactivity of the target compounds to HepG2 (hepatoma cells) was tested by MTT assay. The results showed that the antitumor activity of some of the target compounds in vitro was significantly better than that of Amonafidea, and that compound 7cf7d ~ 7e ~ 11i ~ (11) J had a good inhibitory effect on HepG _ 2 (hepatoma cell line).
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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