【作者】 王玉霞；

【导师】 赵瑾；

【作者基本信息】 河南大学 ， 高分子化学与物理， 2013， 博士

【摘要】 近年来多胺修饰的用于抗肿瘤试剂的多胺缀合物引起人们的广泛关注,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,它们可能具有提高化合物生物活性和细胞选择性的能力。萘酰亚胺类化合物作为抗肿瘤试剂的研究取得了巨大进展,如氨萘非特(amonafide)和米托萘胺(mitonafide)已经进入到了II期临床试验。但是这类化合物也存在着许多不足,如具有神经毒性、肿瘤特异性差等。黄酮类化合物广泛存在于多种植物中,数量种类繁多,结构类型复杂多样,具有许多重要的生理、生化作用,引起了国内外化学家的广泛关注。本论文基于利用多胺分别修饰萘酰亚胺和黄酮这两种药效基团,考察具有细胞毒性的萘酰亚胺和没有细胞毒性的黄酮分别与多胺缀合后活性如何；同时将萘酰亚胺结构和黄酮母核通过碳-碳单键连接后再与多胺缀合。设计合成了三类共62个新型抗肿瘤药物先导,其中59个未见文献报道,评价了部分化合物对4种肿瘤细胞株(MDA-MB-231、HCT-116、HepG2、K562)的细胞毒性、诱导HePG2细胞凋亡的能力、凋亡机制以及体内抗肿瘤活性。研究工作包括以下三个方面：第一部分合成了7种33个酰亚胺-多胺衍生物。首先利用Suzuki偶联反应在萘酰亚胺和邻苯二甲酰亚胺-多胺衍生物的芳环上引入新的苯环,设计合成了9个目标化合物；其次以1,4,5,8-萘二甲酸酐、3,3’,4,4’-邻苯二甲酸酐为原料合成了9个芳香酰二亚胺-多胺衍生物；最后以氨萘菲特和1,8-萘酐为原料合成了10个分子结构中含有乙酰偶联多胺链的萘酰亚胺衍生物和4个乙酰基萘酰亚胺-多胺衍生物。第二部分合成了三类25个黄酮-多胺衍生物。利用具有生物活性的7-羟基黄酮和5,7-二羟基黄酮与多胺反应合成了8个黄酮的Mannich碱类多胺-缀合物；分别通过对5,7-二羟基黄酮进行氨基乙酰化和酯化得到了13个黄酮-多胺缀合物；同时,我们将黄酮骨架和萘酰亚胺骨架结合后与多胺缀合衍生出了4个萘酰亚胺并黄酮-多胺缀合物。第三部分主要研究了萘酰亚胺-多胺衍生物的抗肿瘤活性；初步测试了黄酮-多胺衍生物对HCT-116细胞株的抑制能力；萘酰亚胺并黄酮-多胺缀合物的抗肿瘤活性正在测试中。细胞毒性测试结果表明萘酰二亚胺-多胺衍生物、苯环取代的萘酰亚胺-多胺衍生物、分子结构中含有乙酰基偶联多胺连的萘酰亚胺衍生物均具有一定程度的抗肿瘤活性,部分化合物的活性高于阳性对照品氨萘菲特；部分黄酮-多胺缀合物对HCT-116细胞株的抑制能力优于阳性对照槲皮素。其中代表性化合物21e被证明诱导HePG2细胞凋亡；H22肿瘤模型的体内综合实验表明化合物21e能有效抑制肿瘤细胞并明显延长小鼠寿命,降低血液毒性,这也是阳性对照氨萘菲特最主要的缺陷之一；不过,更有意义的是化合物21e能有效抑制肿瘤细胞的肺转移,这说明多胺与具有药效活性的基团结合后有可能赋予该药效团有趣的生物活性,而萘酰亚胺-多胺缀合物作为抗肿瘤药物是一类非常有前途的先导化合物。更多还原

【Abstract】 The anticancer agents modified by polyamine have attracted widespread attention in recent years, and research has shown that natural or synthetic polyamine has the potential to be an effective targeting vector by using polyamine transporter on the cell membrane, they may have improved the biological activity and cell selectivity of the conjugates coupled by polyamine.Naphthalimides are significant examples of antitumor agents, many of which, such as Amonafide and Mitonafide, have been used in Phase Ⅱ clinical trials. But there are still many problems with them such as neurotoxicity and poor tumor selectivity. Flavonoids are widely distributed in almost all plants owing to huge diversity in the category and configuration. Flavonoids, with unique chemical structures, are bearing many important physiological and biochemical effects. With increasing research of the structure-activity relationship, molecular mechanism of partial pharmacological actions are discovered and this progress acelerates their development.In the dissertation, naphthalimide-polyammine derivatives, flavone-polyamine derivatives and naphthalimide fused flavone-polyamine derivatives were designed and synthesized.62target compounds were synthesized and59have not been reported previously. Antitumor activities of some target compounds were evaluated against MDA-MB-231, HCT-116, HepG2, K562cancer cell lines in vitro. The properties of their induction of apoptosis, antitumor activity in vivo and systemic toxicity were also systematically studied. The research includes mainly three aspects as follows:In the first section seven kinds of33target compounds were designed and synthesized. First a new benzene ring was introduced on the aromatic core of naphthalimide imide-polyamine and phthalimide-polyamine derivatives by Suzuki coupling reaction and nine target compounds were obtained; second, nine aromatic diimide polyamine derivatives were synthesized using1,4,5,8-naphthalenetetracarboxylic dianhydride and3,3’,4,4’biphenyltetracarboxylic diandhydride as raw materials; last, ten alkylamino-acetyl naphthalimide derivatives and four acetyl naphthalimide-polyamine derivatives were designed to couple with different polyamines.In the second section, we synthesized25flavone-polyamine derivatives:four mannich base derivatives of5,7-dihydroxy flavone and four mannich base derivatives of7-hydroxy flavone were geted respectively using5,7-dihydroxy flavone and7-hydroxy flavone as raw materials;13flavone-polyamine conjugates were obtained respectively by the5,7-dihydroxy flavone amino acetylation and esterification; at the same time,4naphthalimide fused flavone-polyamine conjugates were obtained by naphthalimide skeleton combining with flavone skeleton.The third seetion studied the antiproliferative activity, antitumor and apoptosis-inducing function of the naphthalimide-polyamine conjugates; some preliminary tests was maken to investigate the effects of flavone-polyamine derivatives on cancer cell line HCT-116; the pharmacological tests of naphthalimide fused flavone-polyamine conjugates are underway. The in vitro assays revealed that naphthalene diimide polyamine conjugates, benzene substituted naphthalimide polyamine derivatives, alkylaminoacetyl naphthalimide derivatives and the flavone-polyamine derivatives could inhibit the growth of multiple cancer cell lines, some more potent than amonafide.21e, the most potent compound, was verified to efficiently induce HePG2apoptosis in a preliminary mechanistic study. The comprehensive in vivo trials on three H22tumor transplant models demonstrated that21e improved the indexes in terms of inhibitive effect and lifespan extension and reduced the hematotoxicity which is one of main drawbacks of amonafide. More importantly, the obviously elevated ability in preventing lung cancer metastasis was observed, which increased the value of2le as a promising lead compound. This work supported that the versatile function of polyamines may endow some intriguing biological features to the parent drugs.更多还原