天然产物AB5046A、B和Cedarmycins A、B及其衍生物的合成与生物活性
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摘要
以天然产物为先导化合物开发的农药具有高效、抗性发展缓慢、环境相容性好等优点,为了创制开发新的农药品种,本文首先对三酮类天然产物AB5046A、B和含有α-亚甲基-γ-丁内酯结构的天然抗生素cedarmycins A、B进行了首次合成,然后以这四个天然产物为先导化合物设计合成了94个衍生物以及结构新颖的两个副产物,共100个新化合物。它们的结构均经1H NMR和HRMS表征,其中98个化合物还经13C NMR的进一步确认。初步的生物活性测试结果表明,所合成的化合物具有一定的生物活性,结构与活性之间存在一定的构效关系,表明本文涉及的四个天然产物具有作为先导化合物进行进一步研究的价值,为今后更加深入的开展此类工作打下了一定的基础。具体内容如下：
第一部分以具有白化作用的化感抑草活性物质三酮类天然产物AB5046A和B为先导化合物创制开发新型除草剂。首先以较为廉价的间苯三酚为原料通过简单的5步反应可以分别以36%和28%的较高收率首次合成三酮类天然化合物AB5046A和AB5046B。然后对其进行结构改造与修饰,共合成了72个目标化合物,发现部分化合物具有较好的抑制油菜根长和抑制稗草生长的作用,其中和天然产物AB5046A和B结构比较类似的TM-50和TM-51,其活性增加尤为明显。在100μg·ml-1的剂量下,其中TM-50对稗草的褪绿作用达到了81.2%,对油菜根长生长的抑制作用也达到了67.5%。而和AB5046A最为接近的TM-51对油菜根长生长的抑制作用也达到了82.9%,对稗草的褪绿作用也达到了72.0%。重要的是此类化合物的结构和活性之间存在一定的构效关系,具有进一步开发或作为先导化合物研究的价值。
第二部分以天然抗生素cedarmycins A和B作为先导化合物创制开发农用杀菌剂、植物生长调节剂和医用杀菌剂等。首先以廉价的γ-丁内酯为原料通过简单的7步反应可以分别以20%和19%的较高收率首次合成含有α-亚甲基-γ-丁内酯结构的天然产物cedarmycins A和B,成功实现了α-苯硫醚-γ-丁内酯和多聚甲醛发生羟醛缩合反应的改进,且具有一定的实际应用价值。然后合成了24个衍生物以及两个结构新颖的副产物,初步的生物活性测试表明cedarmycins A和B具有一定的农用杀菌活性,cedarmycins A和B及其衍生物的医用杀菌活性正在进一步测定中。
Owing to the advantages of natural products as lead compounds, in this thesis, the natural triketones AB5046A, B and natural antibiotics cedarmycins A, B were designed and synthesized for the first time, then 96 target compounds were designed and synthesized based on them. All compounds have been characterized by 1H NMR and HRMS, and 98 of them have been identified by 13C NMR. Preliminary bioassay shows that all of them possess some extent biological activity, and there exist structure-activity relationships between them. It is proved that they are worth to be studied more deeply.
Firstly, in order to find new herbicide, novel chlorosis-inducing substances, triketones AB5046A and B were firstly prepared from commercially available phloroglucinol in five steps with an overall yield of 36% and 28% respectively. This method was a powerful tool for synthesis of 2-acyl-3,5-dihydroxy-cyclohex-2-ene-l-one derivatives. Then 72 target compounds were designed and synthesized based on the triketones. The in vitro bioassay results demonstrat that some derivates have high herbicidal activity (82.9%), at the dosage of 100μg·mL1 especially their structure were similar with the natural product AB5046A and B. It is important that these triketones herbicides have excellent herbicidal activities, and can be further investigated as lead compounds.
Secondly, in order to find new agricultural fungicide, plant growth regulators, medical fungicide and so on, natural antibiotics cedarmycins A and B were firstly synthesized from commercially available y-butyrolactone in seven steps with an overall yield of 20% and 19% respectively. Then 24 analogues and 2 novel by-products were designed and synthesized based on the antibiotics. The in vitro bioassay results demonstrat that cedarmycins A and B have the certain agricultural fugicidal activity.
Besides, a facile aldol condensation of a-phenylene sulfide-y-butyrolactone and paraformaldehyde promoted by sodium methoxide in methanol was found, and it has a practical application value.
第一部分以具有白化作用的化感抑草活性物质三酮类天然产物AB5046A和B为先导化合物创制开发新型除草剂。首先以较为廉价的间苯三酚为原料通过简单的5步反应可以分别以36%和28%的较高收率首次合成三酮类天然化合物AB5046A和AB5046B。然后对其进行结构改造与修饰,共合成了72个目标化合物,发现部分化合物具有较好的抑制油菜根长和抑制稗草生长的作用,其中和天然产物AB5046A和B结构比较类似的TM-50和TM-51,其活性增加尤为明显。在100μg·ml-1的剂量下,其中TM-50对稗草的褪绿作用达到了81.2%,对油菜根长生长的抑制作用也达到了67.5%。而和AB5046A最为接近的TM-51对油菜根长生长的抑制作用也达到了82.9%,对稗草的褪绿作用也达到了72.0%。重要的是此类化合物的结构和活性之间存在一定的构效关系,具有进一步开发或作为先导化合物研究的价值。
第二部分以天然抗生素cedarmycins A和B作为先导化合物创制开发农用杀菌剂、植物生长调节剂和医用杀菌剂等。首先以廉价的γ-丁内酯为原料通过简单的7步反应可以分别以20%和19%的较高收率首次合成含有α-亚甲基-γ-丁内酯结构的天然产物cedarmycins A和B,成功实现了α-苯硫醚-γ-丁内酯和多聚甲醛发生羟醛缩合反应的改进,且具有一定的实际应用价值。然后合成了24个衍生物以及两个结构新颖的副产物,初步的生物活性测试表明cedarmycins A和B具有一定的农用杀菌活性,cedarmycins A和B及其衍生物的医用杀菌活性正在进一步测定中。
Owing to the advantages of natural products as lead compounds, in this thesis, the natural triketones AB5046A, B and natural antibiotics cedarmycins A, B were designed and synthesized for the first time, then 96 target compounds were designed and synthesized based on them. All compounds have been characterized by 1H NMR and HRMS, and 98 of them have been identified by 13C NMR. Preliminary bioassay shows that all of them possess some extent biological activity, and there exist structure-activity relationships between them. It is proved that they are worth to be studied more deeply.
Firstly, in order to find new herbicide, novel chlorosis-inducing substances, triketones AB5046A and B were firstly prepared from commercially available phloroglucinol in five steps with an overall yield of 36% and 28% respectively. This method was a powerful tool for synthesis of 2-acyl-3,5-dihydroxy-cyclohex-2-ene-l-one derivatives. Then 72 target compounds were designed and synthesized based on the triketones. The in vitro bioassay results demonstrat that some derivates have high herbicidal activity (82.9%), at the dosage of 100μg·mL1 especially their structure were similar with the natural product AB5046A and B. It is important that these triketones herbicides have excellent herbicidal activities, and can be further investigated as lead compounds.
Secondly, in order to find new agricultural fungicide, plant growth regulators, medical fungicide and so on, natural antibiotics cedarmycins A and B were firstly synthesized from commercially available y-butyrolactone in seven steps with an overall yield of 20% and 19% respectively. Then 24 analogues and 2 novel by-products were designed and synthesized based on the antibiotics. The in vitro bioassay results demonstrat that cedarmycins A and B have the certain agricultural fugicidal activity.
Besides, a facile aldol condensation of a-phenylene sulfide-y-butyrolactone and paraformaldehyde promoted by sodium methoxide in methanol was found, and it has a practical application value.
引文
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