本文選題：spirotryprostatins + 芳環(huán)取代�。� 參考：《陜西科技大學(xué)》2017年碩士論文

【摘要】：芳基取代的螺環(huán)吲哚二酮哌嗪類化合物是螺環(huán)吲哚二酮哌嗪類化合物的重要組成部分,而螺環(huán)吲哚二酮哌嗪類化合物中主要以spirotryprostatin類生物堿為代表。研究發(fā)現(xiàn)該類化合物具有很好的生理和藥理活性,尤其對細(xì)胞周期有較好的抑制活性。因此,spirotryprostatin類生物堿可以作為新藥物篩選的先導(dǎo)化合物。本論文對spirotryprostatin類生物堿的骨架進(jìn)行了修飾,首次合成了一系列芳基取代的螺環(huán)吲哚二酮哌嗪類化合物并對其進(jìn)行了結(jié)構(gòu)鑒定和抑菌活性研究。本論文以甘氨酸和靛紅為反應(yīng)原料,分別通過兩步反應(yīng)得到12種席夫堿化合物(偶極體)和13種3-芳亞甲基-2-吲哚酮化合物(親偶極體),選用單一的親偶極體3-苯亞甲基-2-吲哚酮分別和12種席夫堿偶極體化合物在手性配體(S)-TF-BiphamPhos和AgOAc催化下發(fā)生1,3-偶極環(huán)加成反應(yīng)得到12種螺環(huán)吡咯烷中間體,螺環(huán)吡咯烷中間體再與Fmoc-L-pro-Cl發(fā)生酰胺化反應(yīng),然后經(jīng)有機(jī)堿催化脫去保護(hù)基并誘導(dǎo)自發(fā)關(guān)環(huán)得到目標(biāo)產(chǎn)物9a-9e,這5個(gè)化合物皆為新化合物。所有化合物經(jīng)核磁1H-NMR、13C-NMR、紅外光譜、元素分析和HRMS等手段進(jìn)行結(jié)構(gòu)表征,并通過2D NMR和X-ray衍射確定了中間體和目標(biāo)產(chǎn)物的立體構(gòu)型。在抑菌活性實(shí)驗(yàn)中,共選用4株細(xì)菌,分別是兩株革蘭氏陽性菌-金黃色葡萄球菌(Staphy lococcus aureus)和乳酸鏈球菌(Streptococcus lactis),兩株革蘭氏陰性菌-大腸桿菌(Escherichia coli)和綠膿桿菌(Pseudomonas aeruginosa);10株植物病原真菌,分別是小麥赤霉病菌(Fusarium graminearum)、番茄灰霉病菌(Botrytis cinerea)、蘋果樹腐爛病菌(Valsa mali)、煙草赤星病菌(Alternaria alternate)、白菜黑斑病菌(Alternaria brassicae)、玉米大斑病菌(Setosphaeria turcica)、芍藥炭疽病菌(Peony anthracnose)、油菜菌核病菌(Sclerotinia sclerotiorum)、辣椒炭疽病菌(Phytophthora capsici)、葡萄炭疽病菌(Colletotrichum gloeosporioides)。初步的結(jié)果顯示,中間體化合物和目標(biāo)產(chǎn)物都具有一定的抗菌活性,而且目標(biāo)產(chǎn)物的活性優(yōu)于相對應(yīng)的中間體化合物,所有的化合物抗細(xì)菌的活性普遍優(yōu)于抗真菌的活性。這為進(jìn)一步研究該類化合物的抑菌活性的機(jī)理提供了一定的理論基礎(chǔ)。
[Abstract]:Aryl substituted spiroindole piperazine compounds are important components of spirocyclic indoledione piperazine compounds, while spirocyclic indoledione piperazine compounds are mainly represented by spirotryprostatin alkaloids. It was found that these compounds had good physiological and pharmacological activities, especially on cell cycle inhibition. Therefore, spirotryprostatin alkaloids can be used as lead compounds for screening new drugs. In this paper, the skeleton of spirotryprostatin alkaloids was modified and a series of aryl substituted spiroindole piperazine compounds were synthesized for the first time. In this thesis, glycine and indirubin were used as raw materials. Twelve Schiff base compounds (dipoles) and 13 3-arylene methylene-2-indolone compounds (dipolar dipolar compounds) were obtained by two-step reaction respectively, and 12 Schiff bases were obtained using a single dipolar compound, 3-phenylene methyl-2-indole ketone and 12 Schiff bases, respectively. Twelve kinds of spirocyclic pyrrolidine intermediates were synthesized from dipolar compounds catalyzed by chiral ligand Schi-TF-BiphamPhos and AgOAc. The intermediate of spirocyclic pyrrolidine was amidation with Fmoc-L-pro-Cl, then the protective group was removed by organic base and the target product 9a-9e was obtained by spontaneous closing of the ring. The five compounds were all new compounds. All the compounds were characterized by 1H-NMR-13C-NMR-IR, IR, elemental analysis and HRMS. The steric configurations of the intermediates and the target products were determined by 2D NMR and X-ray diffraction. Four strains of bacteria, Staphy lococcus aureus, Streptococcus lactis, Escherichia coli (Escherichia coli) and Pseudomonas aeruginosa (10 strains of Pseudomonas aeruginosa) were selected in the experiment. They are Fusarium graminearum, Botrytis cinereaer, Valsa malium, Alternaria alternateae, Alternaria brassicaeae, Setosphaeria cicaeae, Peony racnoseet, Sclerotinia sclerotiorumum, capsicum. Phytophthora capsicii, Colletotrichum gloeosporioides. The preliminary results showed that both the intermediates and the target products had certain antibacterial activity, and the activity of the target products was better than that of the corresponding intermediates, and the antimicrobial activities of all the compounds were generally superior to those of the antifungal compounds. This provides a theoretical basis for further study on the mechanism of bacteriostatic activity of this kind of compounds.
【學(xué)位授予單位】：陜西科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：O626

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本文編號：1797541