C环不同构型及杂环取代鬼臼类化合物合成及拒食活性研究
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摘要
为了进一步研究鬼臼毒素类化合物结构和杀虫活性的关系,结合近年来杂环农药的发展趋势,本论文在前期研究的基础上设计合成了28种C环修饰鬼臼毒素衍生物,其中18种为含杂环的化合物。合成化合物通过IR、MS、1H NMR和13C NMR对其结构进行确证。同时还收集了3种鬼臼毒素类似物。测试了这31种化合物对3龄粘虫幼虫的拒食活性。取得如下结果:
1.经过文献调研确定:28种合成的化合物中18种含杂环的衍生物为未见报道的新化合物,而其他10种C环修饰的化合物是已报道过的化合物。
2.鬼臼毒素4位引入杂环可以得到比母体化合物活性更高的化合物。4α-吲哚-3-酸-4-脱氧鬼臼酯(I4)其24h AFC50(拒食中浓度)为0.36mg·mL-1,是母体化合物鬼臼毒素拒食毒力的2.03倍,是引入杂环后唯一活性高于母体化合物鬼臼毒素的化合物。其他4位引入杂环后的鬼臼毒素衍生物活性都有所降低。
3.18种含杂环的鬼臼毒素衍生物中,4β位与母体分别以酯键、酰胺键、硫酯键相连引入杂环时,以酯键相连时对粘虫幼虫的拒食活性最高。
4.在合成的所有化合物中24h和48h拒食活性均高于母体化合物鬼臼毒素的只有α-阿朴苦鬼臼毒素(C9),其24h和48h对粘虫幼虫的拒食毒力分别是母体化合物鬼臼毒素的1.30和2.70倍。而β-阿朴苦鬼臼毒素24h拒食活性与鬼臼毒素相当,48h的拒食毒力则是鬼臼毒素的1.78倍,说明C环不饱和可以提高鬼臼毒素的拒食活性。
5.测定了鬼臼毒素4位和2位不同构型的化合物对3龄粘虫幼虫的拒食活性。结果表明:(1)4位为α构型时比4位为β构型时对3龄粘虫幼虫的拒食活性要高;(2)2位为β构型时比2位为α构型时对3龄粘虫幼虫的拒食活性要高。
上述研究结果表明:对鬼臼毒素进行结构修饰可以发现比鬼臼毒素活性更高的化合物;鬼臼毒素杀虫活性结构与抗肿瘤结构有所不同,其作用机制有待进一步研究。
Aiming to study the insecticidal activity , 28 podophyllotoxin derivatives were synthesized based on earlier stage work .Their chemical structure were confirmed by IR,MS,1H-NMR and 13C-NMR.And another 3 podophyllotoxin analogues were collected. The antifeedant activities of 31 compounds against the 3rd-instar larvae of Mythimna separataduring 24h and 48h were assayed with leaf-disk method. The results showed as follows:
1. Among the 28 synthesized compounds ,18 compounds which contained heterocyclic ring were new compounds .
2. The C4 contained heterocyclic ring of podophyllotoxin derivatives can get higher antifeedant activity than podophyllotoxin . The 24h AFC50(concentration for 50% antifeedant activity) against the 3rd larvae of Mythimna separata of 4α-1H-indole-3-acetic acid-4- deoxy- podophyllotoxin ether (I4) was 0.36mg·ml-1 which was 1/2.06 of podophyllotoxin .And the others had lower activity than podophyllotoxin .
3. The antifeedant activity of those compounds which 4βcontained ether bond with heterocyclic ring were the highest in the 18 compounds contained heterocyclic ring.
4. The antifeedant activities ofα-Apopicropodophyllin was the only one higher than podophyllotoxin in all of synthesized compounds against the 3rd-instar Mythimna separata during both 24h and 48h. Its 24h and 48h AFC50 against the 3rd larvae of Mythimna separata was respectively 1/1.30 and 1/2.70 of podophyllotoxin. The 24h antifeedant activities ofβ-Apopicropodophyllin was equal to that of podophyllotoxin against the 3rd-instar Mythimna separata ,but 48h AFC50 was 1/1.78 of podophyllotoxin. The results showed that: not saturation of C ring of podophyllotoxin analogues had very higher activities than others.
5. The antifeedant activities of compounds which had different configuration of C4 and C2 were assayed against the 3rd-instar Mythimna separata .The result showed that: (1) The activity of C4α-configuration podophyllotoxin derivatives were higher than theirβ-configuration analogues (2) The activity of C2β-configuration podophyllotoxin derivatives were higher than theirα-configuration derivatives.
1.经过文献调研确定:28种合成的化合物中18种含杂环的衍生物为未见报道的新化合物,而其他10种C环修饰的化合物是已报道过的化合物。
2.鬼臼毒素4位引入杂环可以得到比母体化合物活性更高的化合物。4α-吲哚-3-酸-4-脱氧鬼臼酯(I4)其24h AFC50(拒食中浓度)为0.36mg·mL-1,是母体化合物鬼臼毒素拒食毒力的2.03倍,是引入杂环后唯一活性高于母体化合物鬼臼毒素的化合物。其他4位引入杂环后的鬼臼毒素衍生物活性都有所降低。
3.18种含杂环的鬼臼毒素衍生物中,4β位与母体分别以酯键、酰胺键、硫酯键相连引入杂环时,以酯键相连时对粘虫幼虫的拒食活性最高。
4.在合成的所有化合物中24h和48h拒食活性均高于母体化合物鬼臼毒素的只有α-阿朴苦鬼臼毒素(C9),其24h和48h对粘虫幼虫的拒食毒力分别是母体化合物鬼臼毒素的1.30和2.70倍。而β-阿朴苦鬼臼毒素24h拒食活性与鬼臼毒素相当,48h的拒食毒力则是鬼臼毒素的1.78倍,说明C环不饱和可以提高鬼臼毒素的拒食活性。
5.测定了鬼臼毒素4位和2位不同构型的化合物对3龄粘虫幼虫的拒食活性。结果表明:(1)4位为α构型时比4位为β构型时对3龄粘虫幼虫的拒食活性要高;(2)2位为β构型时比2位为α构型时对3龄粘虫幼虫的拒食活性要高。
上述研究结果表明:对鬼臼毒素进行结构修饰可以发现比鬼臼毒素活性更高的化合物;鬼臼毒素杀虫活性结构与抗肿瘤结构有所不同,其作用机制有待进一步研究。
Aiming to study the insecticidal activity , 28 podophyllotoxin derivatives were synthesized based on earlier stage work .Their chemical structure were confirmed by IR,MS,1H-NMR and 13C-NMR.And another 3 podophyllotoxin analogues were collected. The antifeedant activities of 31 compounds against the 3rd-instar larvae of Mythimna separataduring 24h and 48h were assayed with leaf-disk method. The results showed as follows:
1. Among the 28 synthesized compounds ,18 compounds which contained heterocyclic ring were new compounds .
2. The C4 contained heterocyclic ring of podophyllotoxin derivatives can get higher antifeedant activity than podophyllotoxin . The 24h AFC50(concentration for 50% antifeedant activity) against the 3rd larvae of Mythimna separata of 4α-1H-indole-3-acetic acid-4- deoxy- podophyllotoxin ether (I4) was 0.36mg·ml-1 which was 1/2.06 of podophyllotoxin .And the others had lower activity than podophyllotoxin .
3. The antifeedant activity of those compounds which 4βcontained ether bond with heterocyclic ring were the highest in the 18 compounds contained heterocyclic ring.
4. The antifeedant activities ofα-Apopicropodophyllin was the only one higher than podophyllotoxin in all of synthesized compounds against the 3rd-instar Mythimna separata during both 24h and 48h. Its 24h and 48h AFC50 against the 3rd larvae of Mythimna separata was respectively 1/1.30 and 1/2.70 of podophyllotoxin. The 24h antifeedant activities ofβ-Apopicropodophyllin was equal to that of podophyllotoxin against the 3rd-instar Mythimna separata ,but 48h AFC50 was 1/1.78 of podophyllotoxin. The results showed that: not saturation of C ring of podophyllotoxin analogues had very higher activities than others.
5. The antifeedant activities of compounds which had different configuration of C4 and C2 were assayed against the 3rd-instar Mythimna separata .The result showed that: (1) The activity of C4α-configuration podophyllotoxin derivatives were higher than theirβ-configuration analogues (2) The activity of C2β-configuration podophyllotoxin derivatives were higher than theirα-configuration derivatives.
引文
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