苯并[c]菲啶和橙酮类化合物的设计、合成与生物活性研究

【作者】 张敏；

【导师】 徐效华；

【作者基本信息】 南开大学 ， 农药学， 2009， 博士

【摘要】 基于从天然活性物质中开发的农药具有高效、抗性发展缓慢和环境相容好等优点,为了开发新的农药品种,本文以生物活性的苯并[c]菲啶型生物碱和橙酮两类天然产物为先导化合物,对其进行结构改造与修饰,共合成了116种不同结构类型的目标化合物,它们的结构均经¹H NMR和HRMS验证,其中的103个化合物还经¹³C NMR验证,部分化合物还得到了IR光谱、2D NMR、X-ray单晶衍射的进一步确认。所合成的化合物具有较好的生物活性,结构与活性之间存在一定的构效关系,为今后的工作打下了一定的基础,具体内容如下:第一部分以我国研制的植物源农药的活性成分血根碱——苯并[c]菲啶型生物碱为先导化合物研究开发新型的杀虫、杀菌剂及植物生长调节剂等,对苯并[c]菲啶骨架进行改造与修饰,主要考查了苯并[c]菲啶环上C（11）-C（12）键的变化、11-位取代基及6-位氨基上取代基的变化对生物活性的影响,共合成了57个目标化合物,发现部分化合物具有较好的杀菌和促进黄瓜子叶生根活性,在50μg·mL^-1的剂量下对花生褐斑的抑制率可以达到70.0%,在10μg·mL^-1的剂量下对黄瓜子叶生根的促进率可以达到88.6%;重要的是,该类化合物还具有强烈的抗癌活性,抑制人乳腺癌（MCF-7）和人肝细胞癌（HepG2）的IC₅₀分别为0.37和1.05μg·mL^-1,具有进一步开发或作为先导化合物继续研究的价值。而且,以叔丁醇钾（t-BuOK）做碱、1,3-二甲基-4H-2-嘧啶酮（DMPU）为溶剂,邻甲基苯腈可发生自缩合反应生成1-氨基-3-（2-甲基苯基）异喹啉,结构得到了X-ray单晶衍射的验证,提供了一条合成3-芳基异喹啉化合物的简便方法。第二部分以化感抑草活性物质——橙酮为先导化合物,研究开发新型的除草剂,主要对橙酮的A环和B环进行结构改造与修饰,重点研究了B环（即Ar部分）的变化对除草活性的影响,优化了合成路线,合成了59个目标化合物,发现了更高除草活性的化合物,在10μg·mL^-1时对油菜根长的抑制率为81.3%;并发现该类化合物具有强烈抑制油菜种子萌发的作用;个别4,6-二乙氧基橙酮降低测试浓度除草活性反而升高,可能存在一种新的除草作用机制,有待于进一步的深入研究。更多还原

【Abstract】 Owing to the advantages of natural active product as lead compounds,in this thesis,116 target compounds were designed and synthesized based on sanguinarine and arone.All compounds have been characterized by ¹H NMR and HRMS,and 103 of them have been identified by ¹³C NMR,and some of them have been further confirmed by IR,2D NMR and X-ray single-crystal diffraction.Preliminary bioassay shows that all of them possess some extent biological activity,and there exist structure-activity relationships between them.Firstly,57 benzo[c]phenanthridine compounds were designed and synthesized based on sanguinarine,a benzo[c]phenanthridine alkaloid,which is a new plant-derived pesticide,and the research was mainly focused on the midification of the bond of C（11）-C（12）,11-substituent and 6-amino of the benzo[c]phenanthridine ring.Preliminary bioassay shows that some of them have high fungicidal activity and promoting cucumber cotyledon root-formation activity at extent experimental dosage. It is important that these benzo[c]phenanthridines have excellent antitumor activities, and can be further investigated as lead compounds.Besides,a facile self-condensation of o-tolunitrile promoted by potassium tert-butanolate in DMPU to synthesize 3-arylisoquinoline derivative was found,and its structure was characterized by X-ray single-crystal diffraction.Secondly,in order to find new herbicide,59 aurones were designed and synthesized based on arone,an allelocherniacal from dee（PI312777）.The research was mainly focused on the midification of A and B rings of aurone and more attention was paid on B ring.The in vitro bioassay result demonstrats that some aurones have high herbicidal activity（81.3%）,at the dosage of 10μg·mL^-1.Moreover,some aurones can strongly inhibit seeds germination of Brassica napus.In addition,the herbicidal activity of 4,6-diethoxyaurones against Brassica napus appears abnormal, this may suggest a new mechanism.更多还原