| 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. |
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