有机磷类、新烟碱类簇合物的设计、合成及其活性评价
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摘要
在生物体系中,多位点结合比单位点结合更具优势。通常多效价能够引起一些蛋白受体的聚合,一些二效价簇合物能引起一些蛋白受体簇合成二聚体,这使得二效价配体比单效价的配体对受体有更强的亲和力,而且利用簇合效应还能找到具选择性的活性分子。通过簇合产生的多效价配体可与受体的多位点相互作用,从而产生协同效应,使其结合力和特异性增强,这样一种原理就是簇合效应。医药研究领域有很多通过簇合效应来增强药物亲和力的事例,但目前国内外关于簇合效应在新农药创制研究中应用却很少报道。鉴于簇合效应已在生物医药研究领域得到成功应用,我们认为将其用于新农药创制研究中也将是一种可行的方案。如果这种猜想得到验证,将为农药新品种的开发提供一条新途径。
有机磷化合物是典型的乙酰胆碱酯酶(AChE)抑制剂。乙酰胆碱酯酶活性位点的结构表明,在其两端有特异性位点,在乙酰胆碱酯酶峡口的入口处主要由氨基酸Tyr70、Tyr121、Trp279和Asp72组成,这些氨基酸组成了AChE的外周阴离子位点。通过连接乙酰胆碱酯酶的催化位点和外周位点,科学家们合成了一系列具有生物活性的乙酰胆碱酯酶双位点抑制剂。根据簇合效应,结合乙酰胆碱酯酶结构信息,我们设计并合成了20个有机磷的二效价簇合物,期望能同时结合乙酰胆碱酯酶的催化位点和外周位点,旨在找到更具亲和力的乙酰胆碱酯酶抑制剂。
对所合成的目标化合物进行了生物测定。初步结果显示,二效价有机磷簇合物对家蝇和蚜虫表现出一定的杀虫活性。点滴实验测得化合物PSG2(6a)、PSG3(6b)、PSDG(6c)对家蝇的LD50值分别为1.71,1.74,1.51μg/头;PSOL4(3i)、SPhOL4(9i)、SPhAL4(9b)分别为1.72、3.64、0.788μg/头;SPhAL7(9e)、SPhAL8(9f)、SPhAL9(9g)分别为1.15、2.62、19.0μg/头。不过二效价有机磷簇合物对甜菜夜蛾、棉铃虫、红蜘蛛等杀虫活性不是很理想。
此外,我们又合成7个二效价吡虫啉簇合物,所有目标化合物通过1H-NMR和元素分析确认。初步生测结果表明部分目标化合物具有一定的杀虫活性,在100mg/L浓度下,IMAC4(12a)和IMAC6(12c)对麦长管蚜的平均致死率达78.4%和77.3%(24h),IMAC4(12a)对东亚飞蝗的致死率达77.5%(72h),但都低于对照药剂吡虫啉。
以碘化乙酰硫代胆碱为底物,二硫双对硝基苯甲酸(DTNB)为显色剂,我们用传统的Ellman分光光度法,研究了二效价有机磷簇合物对家蝇AChE的抑制活性。化合物SPhAL7(9e)、SPhAL8(9f)、PSOL4(3i)、PSG3(6b)、PSDG(6c)、乙硫磷对乙酰胆碱酯酶的IC50分别为0.021、0.830、0.484、14.581、10.521、0.044mM。可以看出化合物SPhAL7(9e)、SPhAL8(9f)、PSOL4(3i)对乙酰胆碱酯酶有较好的抑制活性,尤其是SPhAL7(9e)对乙酰胆碱活性的抑制效果比乙硫磷还好。本文利用簇合效应原理,合成了一些对乙酰胆碱酯酶抑制活性较好的化合物,为今后的研究工作提供了很好的基础,值得进一步深入开展这方面的研究。
In biological systems, multivalent binding provides a broad range of benefits that are not achievable with the corresponding monovalent interactions. Multivalent interactions induce receptor clustering, such as the bivalent ligand mediated protein dimerization, wich would result in bivalent interaction is much tighter than monovalent interaction. And multivalent interactions can enhance ligand selectivity. Design and synthesis multivalent ligand to interact with the multiple sites of the receptor, in order to causes synergistic effect, result in a high-affinity system and enhance selectivity of the ligand, this theoretical hypothesis was described as the“cluster effect”. The activities of some multivalent drug molecules were significantly enhanced by their cluster effect. However, little has been reported about the applications of cluster effect in new pesticide discovery. Since the cluster effect has been applied in drug design, we believe that the theoretical hypothesis can serve as reference and guidance for the discovery of new agrochemical.
Organophosphorusac act as classical acetylcholinesterase(AChE) inhibitors. The geometry of the active-site gorge of AChE, with specific sites at its two extremities, Tyr70, Tyr121, Trp279 and Asp72 lining the entrance gorge of AChE, that is peripheral anionic site of AChE(PAS). Through binding to both catalytic and peripheral sites of the enzyme, a series of dual binding site AChE inhibitors have been designed and synthesized.The cluster effect, combined with information about the structure of acetylcholinesterase, led us to design and synthesize 20 bivalent organphosphorus compounds as potential acetylcholinesterase inhibitors. We anticipated that the target compounds would bind to both catalytic and peripheral sites of the enzyme that leading to more stable AChE-organphosphorus complexes.
The insecticidal activity of all target compounds was evaluated. In the preliminary bioassay test,some bivalent organphosphorus compounds have been showed insecticidal activity against cotton aphid(Aphis gossypii) and housefly(Musca domestica Linnaeus). Topical application method was used to test medium lethal quantity of Musca domestica, LD50 values of PSG2(6a), PSG3(6b) and PSDG(6c) were 1.71, 1.74, 1.51μg/No.;LD50 values of PSOL4(3i), SPhOL4(9i) and SPhAL4(9b) were 1.72, 3.64, 0.788μg/No.;LD50 values of SPhAL7(9e), SPhAL8(9f) and SPhAL9(9g) were 1.15, 2.62, 19.0μg/No. However, the activity of bivalent organphosphorus compounds was not so good on Helicoverpa armigera, Spodoptera exigua and Tetranychus cinnabarinus.
In search for neonicotinoid insecticides with high activities, seven novel bivalent compounds were prepared from imidacloprid as precursor compound. Their structures were confirmed by 1H NMR and elemental analysis. The preliminary bioassay indicated that these compounds showed insecticidal activities. The average mortality of IMAC4 (12a)and IMAC6(12c) to macrosiphum avenae at the concentration of 100mg/L reached 78.4% and 77.3% respectively(24h); The mortality of IMAC4(12a) to locusta migratoria manilenis at the concentration of 100mg/L reached 77.5%(72h). But the activity of these compouds was not as good as imidacloprid, the control pesticide.
We used acetylthiocholine idodide as the substrate of the enzymatic reaction and 5,5'-dithio-bis (2-nitrobenzoic acid) for the measurement of cholinesterase activity by the conventional spectrophotometric method of Ellman. The IC50 values of SPhAL7(9e), SPhAL8(9f), PSOL4(3i), PSG3(6b), PSDG(6c) and ethion were 0.021, 0.830, 0.484, 14.581, 10.521, 0.044mM respectively, the compounds SPhAL7(9e), SPhAL8(9f) and PSOL4(3i) showed good AchE inhibitory activity, especially SPhAL7(9e) was very good, even better than ethion. In summary, we designed and synthesised some bivalent compounds as potential AChE inhibitors by cluster effect, the study provides a basis for the further related work and were worth further studying.
有机磷化合物是典型的乙酰胆碱酯酶(AChE)抑制剂。乙酰胆碱酯酶活性位点的结构表明,在其两端有特异性位点,在乙酰胆碱酯酶峡口的入口处主要由氨基酸Tyr70、Tyr121、Trp279和Asp72组成,这些氨基酸组成了AChE的外周阴离子位点。通过连接乙酰胆碱酯酶的催化位点和外周位点,科学家们合成了一系列具有生物活性的乙酰胆碱酯酶双位点抑制剂。根据簇合效应,结合乙酰胆碱酯酶结构信息,我们设计并合成了20个有机磷的二效价簇合物,期望能同时结合乙酰胆碱酯酶的催化位点和外周位点,旨在找到更具亲和力的乙酰胆碱酯酶抑制剂。
对所合成的目标化合物进行了生物测定。初步结果显示,二效价有机磷簇合物对家蝇和蚜虫表现出一定的杀虫活性。点滴实验测得化合物PSG2(6a)、PSG3(6b)、PSDG(6c)对家蝇的LD50值分别为1.71,1.74,1.51μg/头;PSOL4(3i)、SPhOL4(9i)、SPhAL4(9b)分别为1.72、3.64、0.788μg/头;SPhAL7(9e)、SPhAL8(9f)、SPhAL9(9g)分别为1.15、2.62、19.0μg/头。不过二效价有机磷簇合物对甜菜夜蛾、棉铃虫、红蜘蛛等杀虫活性不是很理想。
此外,我们又合成7个二效价吡虫啉簇合物,所有目标化合物通过1H-NMR和元素分析确认。初步生测结果表明部分目标化合物具有一定的杀虫活性,在100mg/L浓度下,IMAC4(12a)和IMAC6(12c)对麦长管蚜的平均致死率达78.4%和77.3%(24h),IMAC4(12a)对东亚飞蝗的致死率达77.5%(72h),但都低于对照药剂吡虫啉。
以碘化乙酰硫代胆碱为底物,二硫双对硝基苯甲酸(DTNB)为显色剂,我们用传统的Ellman分光光度法,研究了二效价有机磷簇合物对家蝇AChE的抑制活性。化合物SPhAL7(9e)、SPhAL8(9f)、PSOL4(3i)、PSG3(6b)、PSDG(6c)、乙硫磷对乙酰胆碱酯酶的IC50分别为0.021、0.830、0.484、14.581、10.521、0.044mM。可以看出化合物SPhAL7(9e)、SPhAL8(9f)、PSOL4(3i)对乙酰胆碱酯酶有较好的抑制活性,尤其是SPhAL7(9e)对乙酰胆碱活性的抑制效果比乙硫磷还好。本文利用簇合效应原理,合成了一些对乙酰胆碱酯酶抑制活性较好的化合物,为今后的研究工作提供了很好的基础,值得进一步深入开展这方面的研究。
In biological systems, multivalent binding provides a broad range of benefits that are not achievable with the corresponding monovalent interactions. Multivalent interactions induce receptor clustering, such as the bivalent ligand mediated protein dimerization, wich would result in bivalent interaction is much tighter than monovalent interaction. And multivalent interactions can enhance ligand selectivity. Design and synthesis multivalent ligand to interact with the multiple sites of the receptor, in order to causes synergistic effect, result in a high-affinity system and enhance selectivity of the ligand, this theoretical hypothesis was described as the“cluster effect”. The activities of some multivalent drug molecules were significantly enhanced by their cluster effect. However, little has been reported about the applications of cluster effect in new pesticide discovery. Since the cluster effect has been applied in drug design, we believe that the theoretical hypothesis can serve as reference and guidance for the discovery of new agrochemical.
Organophosphorusac act as classical acetylcholinesterase(AChE) inhibitors. The geometry of the active-site gorge of AChE, with specific sites at its two extremities, Tyr70, Tyr121, Trp279 and Asp72 lining the entrance gorge of AChE, that is peripheral anionic site of AChE(PAS). Through binding to both catalytic and peripheral sites of the enzyme, a series of dual binding site AChE inhibitors have been designed and synthesized.The cluster effect, combined with information about the structure of acetylcholinesterase, led us to design and synthesize 20 bivalent organphosphorus compounds as potential acetylcholinesterase inhibitors. We anticipated that the target compounds would bind to both catalytic and peripheral sites of the enzyme that leading to more stable AChE-organphosphorus complexes.
The insecticidal activity of all target compounds was evaluated. In the preliminary bioassay test,some bivalent organphosphorus compounds have been showed insecticidal activity against cotton aphid(Aphis gossypii) and housefly(Musca domestica Linnaeus). Topical application method was used to test medium lethal quantity of Musca domestica, LD50 values of PSG2(6a), PSG3(6b) and PSDG(6c) were 1.71, 1.74, 1.51μg/No.;LD50 values of PSOL4(3i), SPhOL4(9i) and SPhAL4(9b) were 1.72, 3.64, 0.788μg/No.;LD50 values of SPhAL7(9e), SPhAL8(9f) and SPhAL9(9g) were 1.15, 2.62, 19.0μg/No. However, the activity of bivalent organphosphorus compounds was not so good on Helicoverpa armigera, Spodoptera exigua and Tetranychus cinnabarinus.
In search for neonicotinoid insecticides with high activities, seven novel bivalent compounds were prepared from imidacloprid as precursor compound. Their structures were confirmed by 1H NMR and elemental analysis. The preliminary bioassay indicated that these compounds showed insecticidal activities. The average mortality of IMAC4 (12a)and IMAC6(12c) to macrosiphum avenae at the concentration of 100mg/L reached 78.4% and 77.3% respectively(24h); The mortality of IMAC4(12a) to locusta migratoria manilenis at the concentration of 100mg/L reached 77.5%(72h). But the activity of these compouds was not as good as imidacloprid, the control pesticide.
We used acetylthiocholine idodide as the substrate of the enzymatic reaction and 5,5'-dithio-bis (2-nitrobenzoic acid) for the measurement of cholinesterase activity by the conventional spectrophotometric method of Ellman. The IC50 values of SPhAL7(9e), SPhAL8(9f), PSOL4(3i), PSG3(6b), PSDG(6c) and ethion were 0.021, 0.830, 0.484, 14.581, 10.521, 0.044mM respectively, the compounds SPhAL7(9e), SPhAL8(9f) and PSOL4(3i) showed good AchE inhibitory activity, especially SPhAL7(9e) was very good, even better than ethion. In summary, we designed and synthesised some bivalent compounds as potential AChE inhibitors by cluster effect, the study provides a basis for the further related work and were worth further studying.
引文
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