新烟碱类化合物结构衍生和生物活性测试研究
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摘要
新烟碱类化合物作用于昆虫烟碱型乙酰胆碱受体,其作用机制独特,与常规杀虫剂无交互抗性,具有高效、广谱及良好的根部内吸性、触杀和胃毒作用,对哺乳动物毒性低、对环境安全,已经引起了人们的广泛关注,在30年之内共有七个商品化的产品上市,占据了杀虫剂市场超过20%的份额。然而近年来该类化合物的过量频繁使用,已使多种害虫产生了不同程度的抗性,而且不同种类的新烟碱杀虫剂也产生了一定的交互抗性。本论文从商品化新烟碱类化合物结构出发,分别对开环和闭环类化合物进行结构改造,寻找高活性化合物的同时对构效关系进行研究,为该类化合物的进一步修饰提供一定理论根据。
1)在开环新烟碱类结构中引入具有医药活性的1,4-二氢吡啶类活性基团,并对合成的新化合物分别进行杀虫活性测试和抗癌活性测试。目标化合物对苜蓿蚜、粘虫和褐飞虱具有一定的杀死率,对五种癌细胞也表现出一定的抑制作用,。
2)设计合成了含氮杂1,3-二烯结构的开环新烟碱化合物,目标化合物对苜蓿蚜的LCso值均在30 ppm之下,部分化合物还具有一定的除草活性。与相应的闭环化合物相比,环的打开对化合物活性影响非常大。
3)从不稳定1-氮杂二烯中间体出发,利用Aza-Diels-Alder反应(ADAR)构建四氢吡啶环。该ADAR反应克服了此类反应需催化剂或高压催化、产率低等缺点,可在无催化条件下快速高效得到目标化合物,对反应条件也进行了优化。部分目标化合物对苜蓿蚜表现出高活性,与商品化产品吡虫啉活性相当；目标产物的光稳定性和水稳定性均有明显改善。
4)对ADAR反应进行多组分反应研究的同时,利用不同底物对目标产物的五个结构片段进行修饰,合成得到一系列化合物并进行生物活性测试。生测结果表明五个部位中有三个为关键影响位点,导致活性差异。另选择一个产物进行手性拆分得到四个光学纯异构体,并测试相应化合物杀虫活性。以目标产物中活性化合物的PIC5o作为因变量,选取DS软件遗传函数算法(GFA模型)中其自身物性参数和预测生物特性参数为自变量,进行多元线回归分析,得到两类较为合理的回归方程。
Acting on insect nicotinic acetylcholine receptors (nAChRs), neonicotinoids have attracted worldwide attention by virtue of novel modes of action, no cross-resistance with conventional insecticides, broad insecticidal spectra, excellent root uptake properties, contact and stomach toxicity, low mammalian toxicity and environmental friendly property. Seven commercial products were introduced to market during the past 30 years, which shared 20% of the crop protection industry. However, significant increases in resistance and cross-resistance were observed in a range of species after frequent field applications. Based above, series of acyclic and cyclic neonicotinoids derivatives had been designed in this thesis to seek high active compounds, the structure activity relationships had also been studied for further research.
1) Pharmaceutical active 1,4-dihydropyridine fragment was introduced to the acyclic neonicotinoids. The insecticidal and anti-cancer assay indicated that synthesized compounds showed good activities against cowpea aphids(Aphis Craccivora Koch), armyworm (Pseudaletia Separate Walker) and brown planthopper (Nilaparvala lugens(Stal)), and certain activities to five tumor cells (Hela, HCT116, A549, K562 and MCF-7).
2) Acyclic compounds with N-aza-1,3-diene structure were designed and synthesized. The observed LC50 value against aphids was below 30 ppm, while some compounds showed certain herbicidal acticvities. It indicated that the ring opening had a great impact on the activities.
3) Tetrahydropyridine was applied to modify the unstable active intermediates by aza-Diels-Alder Reaction (ADAR). The use of common ADAR is limited due to the need for catalysis and low yield, while our particular reaction was easy to proceed with high yield under no catalyst, the reaction conditions were optimized as well. Targeted compounds were endowed with excellent insecticidal activities against cowpea aphids, some of those rivaled imidacloprid. Meanwhile, photo-stability and water stability study indicated the improvement of target compound against the unstable intermediate.
4) The five segments of ADAR products were modified by multi-component reactions (MCRs) to afford a series of compounds and evaluated their insecticidal activities. Bioassay indicated three of the five segments were the key factors response for activity difference. Then one product was chirally separated to get four optically pure isomers and test their insecticidal activities. Afterwards, two kinds of regression equation were obtained using genetic function approximation (GFA) as QSAR models.
1)在开环新烟碱类结构中引入具有医药活性的1,4-二氢吡啶类活性基团,并对合成的新化合物分别进行杀虫活性测试和抗癌活性测试。目标化合物对苜蓿蚜、粘虫和褐飞虱具有一定的杀死率,对五种癌细胞也表现出一定的抑制作用,。
2)设计合成了含氮杂1,3-二烯结构的开环新烟碱化合物,目标化合物对苜蓿蚜的LCso值均在30 ppm之下,部分化合物还具有一定的除草活性。与相应的闭环化合物相比,环的打开对化合物活性影响非常大。
3)从不稳定1-氮杂二烯中间体出发,利用Aza-Diels-Alder反应(ADAR)构建四氢吡啶环。该ADAR反应克服了此类反应需催化剂或高压催化、产率低等缺点,可在无催化条件下快速高效得到目标化合物,对反应条件也进行了优化。部分目标化合物对苜蓿蚜表现出高活性,与商品化产品吡虫啉活性相当；目标产物的光稳定性和水稳定性均有明显改善。
4)对ADAR反应进行多组分反应研究的同时,利用不同底物对目标产物的五个结构片段进行修饰,合成得到一系列化合物并进行生物活性测试。生测结果表明五个部位中有三个为关键影响位点,导致活性差异。另选择一个产物进行手性拆分得到四个光学纯异构体,并测试相应化合物杀虫活性。以目标产物中活性化合物的PIC5o作为因变量,选取DS软件遗传函数算法(GFA模型)中其自身物性参数和预测生物特性参数为自变量,进行多元线回归分析,得到两类较为合理的回归方程。
Acting on insect nicotinic acetylcholine receptors (nAChRs), neonicotinoids have attracted worldwide attention by virtue of novel modes of action, no cross-resistance with conventional insecticides, broad insecticidal spectra, excellent root uptake properties, contact and stomach toxicity, low mammalian toxicity and environmental friendly property. Seven commercial products were introduced to market during the past 30 years, which shared 20% of the crop protection industry. However, significant increases in resistance and cross-resistance were observed in a range of species after frequent field applications. Based above, series of acyclic and cyclic neonicotinoids derivatives had been designed in this thesis to seek high active compounds, the structure activity relationships had also been studied for further research.
1) Pharmaceutical active 1,4-dihydropyridine fragment was introduced to the acyclic neonicotinoids. The insecticidal and anti-cancer assay indicated that synthesized compounds showed good activities against cowpea aphids(Aphis Craccivora Koch), armyworm (Pseudaletia Separate Walker) and brown planthopper (Nilaparvala lugens(Stal)), and certain activities to five tumor cells (Hela, HCT116, A549, K562 and MCF-7).
2) Acyclic compounds with N-aza-1,3-diene structure were designed and synthesized. The observed LC50 value against aphids was below 30 ppm, while some compounds showed certain herbicidal acticvities. It indicated that the ring opening had a great impact on the activities.
3) Tetrahydropyridine was applied to modify the unstable active intermediates by aza-Diels-Alder Reaction (ADAR). The use of common ADAR is limited due to the need for catalysis and low yield, while our particular reaction was easy to proceed with high yield under no catalyst, the reaction conditions were optimized as well. Targeted compounds were endowed with excellent insecticidal activities against cowpea aphids, some of those rivaled imidacloprid. Meanwhile, photo-stability and water stability study indicated the improvement of target compound against the unstable intermediate.
4) The five segments of ADAR products were modified by multi-component reactions (MCRs) to afford a series of compounds and evaluated their insecticidal activities. Bioassay indicated three of the five segments were the key factors response for activity difference. Then one product was chirally separated to get four optically pure isomers and test their insecticidal activities. Afterwards, two kinds of regression equation were obtained using genetic function approximation (GFA) as QSAR models.
引文
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