【作者】 臧传丽；

【导师】 李圣坤；

【作者基本信息】 南京农业大学 ， 农业硕士（专业学位）， 2018， 硕士

【摘要】 吲咮二酮哌嗪类化合物具有广泛的生物活性,如抗癌活性、免疫调节活性、抗菌活性、和杀虫活性等,也可以作为植物生长调节剂。Brevianamide F本身可以做为新型天然植物生长抑制剂,也是很多复杂吲咮二酮哌嗪生物碱的前体;改变氨基酸而得到的类似物表现出抑菌和抗癌等多样的生物活性。我们基于Brevianamide F,设计合成了新型的吲哚二酮哌嗪类天然生物碱及类似物,探讨了不同的构型对该化合物生物活性的影响,取得的结果如下(1)以廉价易得的色氨酸缬氨酸为原料,通过氨基酸保护和缩合等关键步骤,实现了天然产物(吲咮-N-异戊烯基)-环色氨酸/缬氨酸二酮哌嗪A的合成。共制备两对共四个立体异构体,通过电喷雾离子源质谱(ESI-MS)以及氢核磁共振谱(1H-NMR)、碳核磁共振谱(13C-NMR)等进行结构鉴定,测试了这些化合物对小麦赤霉病菌(Fusariumgraminearum)、小麦全蚀病菌(Gaeumannomycesgramini)、草莓灰霉病菌(Botrytiscinerea)、辣椒疫霉病菌(Phytophythora capsici)、水稻纹枯病菌(Rhizoctoniasolani)、油茱菌核病菌(Sclerotinia sclerotiorum)、水稻稻瘟病菌(Piricularia oryzae)共7种重要的植物病原菌的离体抑菌活性,发现当氨基酸为D构型时,抑菌活性要优于其他构型。对水稻瘟孢子萌发的抑制作用与菌丝生长速率法结果一致,得出(9R,12S)-立体异构体(1a)、(9R,12R)-立体异构体(1b)、(9S,12R)-立体异构体(1c)、(9S,12S)-立体异构体(1d)对稻瘟病孢子萌发的抑制率分别为68.84%、78.45%、63.54%和59.54%,结果显示当氨基酸的构型均为D构型时其抑制率最高。(2)以抑菌活性较好地的手性化合物1b为先导结构,进行了结构优化并探讨开环结构与闭环结构对活性的影响。共计合成25个化合物,通过电喷雾离子源质谱(ESI-MS)以及氢核磁共振谱(1H-NMR)、碳核磁共振谱(13C-NMR)等进行结构鉴定,并通过菌丝生长速率法测定化合物对小麦赤霉病菌、小麦全蚀病菌、草莓灰霉病菌、辣椒疫霉病、水稻纹枯病菌、油菜菌核病菌和水稻稻瘟病菌共7种重要的植物病原真菌的离体抑菌活性。结果表明该类化合物表现出明显的手性效应,当吲咮和二酮哌嗪环上的氨基酸的构型均为D构型时抑菌活性要明显优于其他三种异构体,化合物2g对油菜菌核病菌的抑菌活性要优于1b,在活体水平上检测了油菜菌核病菌的防效,实验结果表明2g在100 mg/L时,保护效果为41.9%,低于阳性对照多菌灵(54.4%)。(3)测定了化合物1b、2g、2j对稗草和鳢肠的根和芽长的调节实验,结果显示在浓度为100 mg/L时,化合物2g对鳢肠根的抑制率达到46.4%。化合物2j对稗草根的生长具有促进作用,在浓度为200 mg/L到0.125 mg/L下对稗草根长均具有促进作用。本文完成了天然产物(吲咮-N-异戊烯基)-环色氨酸/缬氨酸二酮哌嗪四种异构体的合成,合成了 Brevianamide F类似物30个,其中新化合物27个。完成了结构鉴定及抑菌构效关系研究和植物生长调节活性研究,为基于吲咮二酮哌嗪的新型手性生物碱农药的开发打下基础。更多还原

【Abstract】 Indole diketopiperazines have a wide range of biological activities,including anticancer activity,immunomodulatory activity,antifungal activity and insecticidal activity.They can also act as plant growth regulators.Brevianamide F was reported as a new natural plant growth inhibitor and could serve as scaffold for many complex indole diketopiperazines.Variation of the amino acid precursors will lead to many diketopiperazines exhibiting various biological activities.Herein,four stereoisomers of the natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine were accomplished.Based on the these natural products and Brevianamide F,design and synthesis of novel indole diketopiperazines alkaloids and analogues were carried out.Biological exploration and SAR were also conducted,and the results obtained are as follows:(1)Synthesis of the four stereoisomers of natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine was achieved from cheap and easily available tryptophan and valine in 5 steps.The key steps consisted of protection and condensation of different amino acids,followed by deprotection and cyclization.The structures were identified by electrospray ionization mass spectrometry(ESI-MS),1H-Nuclear Magnetic Resonance(1H-NMR)Spectroscopy,13C-Nuclear Magnetic Resonance(13C-NMR)Spectroscopy.The in vitro antifungal bioactivity of these compounds were tested against 7 important plant pathogens including Fusarium graminearum.Gaeumannomyces gramini,Botrytis cinerea,Phytophythora capsici,Rhizoctonia solani,Sclerotinia sclerotiorum,Pyricularia oryzae.The antifungal activity of the stereoisomer from the amino acids is superior to the enantiomer and diastereoisomers.The results from spore germination against Pyricularia oryzae was consistent with that of mycelium growth rate method.The(9R,12S)-stereoisomer(1a),(9R,12R)-stereoisomer(1b),(95,12R)-stereoisomer(1c)and(9S,12S)-stereoisomers(1d)were obtained and tested against Pyricularia oryzae with the inhibitory rates of 68.84%,78.45%,63.54%and 59.54%,respectively.(2)with the(9R,127R)-stereoisomer(1b)as a lead,Structure optimization was carried out and investigated considering the effects of the open-loop and closed-loop structures on the activity.25 novel indole diketopiperazines were synthesized and characterized by electrospray ionization mass spectrometry(ESI-MS),1H-NMR and 13C-NMR.The antifungal activity was conducted against 7 important plant pathogens,including Fusarium graminearum.Gaeumannomyces gramini,Botrytis cinerea,Phytophythora capsici,Rhizoctonia solani,Sclerotinia sclerotiorum,Pyricularia oryzae.obvious effect of substituents and chirality on bioactivity were detected.Compound 2g was selected as an antifungal lead against Sclerotinia sclerotiorum,the in vivo biotest also showed that compound 2g possessed good preventative efficacy at 100 mg/L against Sclerotinia sclerotiorum with the inhibitory rate of 41.9%.(3)Regulatory bioactivities of compounds 1b,2g,and 2j were measured on the roots and shoots of Echinochloa crus-galli and Eclipta prostrata.The results showed that compound 2g can inhibit the growth of roots of Eclipta prostrata significantly at the concentration of 100 mg/L,with the inhibitory rate of 46.4%.Compound 2j had a promoting effect on the growth of roots of Eclipta prostrata,with the concentration ranging from 200 mg/L to 0.125 mg/L,which was different from that of the positive control indole acetic acid,changing the effect from inhibition to promotion with the reduction of concentration.In summary,synthesis of the four stereoisomers of the natural product(indole-N-isoprenyl)tryptophan-valine diketopiperazine was completed 30 indole diketopiperazines were synthesized based on Brevianamide F and(indole-N-isoprenyl)tryptophan-valine diketopiperazine including 27 new compounds.antifungal activities,structure-activity relationship and plant growth regulatory activities were also explored.This work laid a good foundation for the discovery of new chiral diketopiperazines as potential agrochemicals.更多还原