本文選題：第二信使 + 環(huán)二核苷酸�。� 參考：《河南師范大學》2017年碩士論文

【摘要】：環(huán)二核苷酸是微生物的第二信使,在調(diào)節(jié)病原微生物的致病性和形態(tài)方面具有重要作用。環(huán)二核苷酸可被人體的免疫系統(tǒng)識別以抵抗病原微生物的進攻,而且能通過刺激腫瘤患者的免疫系統(tǒng)細胞產(chǎn)生細胞因子而殺傷腫瘤細胞。本論文提供了一種新的合成環(huán)二核苷酸類化合物的方法,該合成路線條件溫和、操作簡單、成本較低。本論文的工作主要包括以下三個部分:在第一部分的工作中,以鳥苷為原料,用三甲基氯硅烷對糖環(huán)上的羥基和鳥嘌呤上的氨基進行保護,然后用異丁酰氯選擇性進攻氨基,再脫去三甲基硅基,得到N2-異丁酰基鳥苷。與DMTrC1反應,對5'-羥基進行保護;與TBDMSCl反應,對糖環(huán)上的3'-羥基進行保護;經(jīng)過亞磷酰化反應,得到3'-叔丁基二甲基硅烷-2'-[(2-氰基乙氧基)-N,N-二異丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N2-異丁酰基鳥苷2-12。以腺苷為原料,與乙酸酐反應,對腺苷糖環(huán)上的2',3',5'-羥基進行保護;經(jīng)過苯乙酰化反應,對腺嘌呤上的氨基進行保護,脫去乙酸酐,得到N6-苯甲�；佘铡Ｓ肈MTrC1保護5'-羥基,TBDMSCl保護2'-羥基,乙酰丙�；Ｗo3'-羥基,隨后脫去5'-羥基的保護基,制備了重要中間體2'-叔丁基二甲基硅烷-3'-乙酰丙酰基-5'-(4,4'-二甲氧基三苯基甲基)-N6-苯甲�；佘�2-7。中間體2-12和2-7在乙腈和1H-四氮唑的作用下耦合,三價磷被氧化后生成2-13,收率是89%。3'-/5'-脫保護,純化,在1H-四氮唑和雙(二異丙基氨基)(2-氰基乙氧基)膦的作用下原位分子內(nèi)環(huán)化,經(jīng)氧化后生成化合物2-14,收率80%,再脫除保護基得到目標化合物2',3'-cGAMP。第二部分的工作中,以中間體2-10為原料,通過和亞磷�；噭┓磻蓙喠柞０分虚g體2'-叔丁基二甲基硅烷-3'-[(2-氰基乙氧基)-N,N-二異丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N2-異丁酰基鳥苷3-1,中間體3-1和2-7在乙腈和1H-四氮唑的作用下成耦合,氧化后的產(chǎn)率是95%,再經(jīng)過3'-/5'-脫保護,原位分子內(nèi)環(huán)化,氧化后收率是86%,再脫保護最終得到目標化合物3',3'-cGAMP。第三部分的工作中,以中間體2-5為原料,通過和亞磷酰化試劑反應生成亞磷酰胺中間體2'-叔丁基二甲基硅烷-3'-[(2-氰基乙氧基)-N,N-二異丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N6-苯甲�；佘�4-1,中間體4-1和2-7在乙腈和1H-四氮唑的作用下耦合,用環(huán)化試劑環(huán)化鏈狀二核苷單磷酸,氧化和純化后的產(chǎn)率為83%,脫除保護基團后得到目標化合物3',3'-c-di-AMP。
[Abstract]:Cyclic dinucleotide is the second messenger of microorganism and plays an important role in regulating the pathogenicity and morphology of pathogenic microorganisms. Cyclic dinucleotides can be recognized by the human immune system to resist the attack of pathogenic microorganisms, and can kill tumor cells by stimulating the immune system cells of tumor patients to produce cytokines. In this paper, a new method for the synthesis of cyclic dinucleotides is proposed. The synthetic conditions are mild, the operation is simple and the cost is low. The main work of this paper includes the following three parts: in the first part of the work, using guanosine as the raw material, trimethylchlorosilane was used to protect the hydroxyl group on the sugar ring and the amino group on the guanine, and then to attack the amino group selectively with isobutylol chloride. Then trimethylsilyl was removed to obtain N _ 2-isobutyloyl guanosine. In the reaction with DMTrC1, the 5- hydroxyl group is protected; the 3- hydroxyl group on the sugar ring is protected by the reaction with TBDMSCl; after the phosphorous acylation reaction, 3- tert-Ding Ji dimethylsilane-2-[2-cyanoethoxy-N- (N-)-diisopropyl amino]-5-(5)-(4 -) -dimethoxy triphenyl methyl-N _ 2-butyloyl guanosine 2-12 were obtained. Using adenosine as raw material and acetic anhydride as raw material, we protect the 2 ~ (2 +) ~ (3) ~ (3 +) ~ (5) -hydroxyl group on the adenosine ring, and after the acetylation of benzene, protect the amino group from adenine, remove acetic anhydride, and obtain N _ (6-benzoyl) adenosine (N6-benzoyl adenosine). DMTrC1 was used to protect the 2-hydroxyl group from TBDMSCl, and 3-hydroxyl group from acetyl group to protect the 2-hydroxyl group, and then to remove the protective group from the 5-hydroxyl group. An important intermediate 2- tert-Ding Ji dimethyl silane-3-acetyl-5-propanoyl-5-dimethoxy-triphenyl-methyl-N-6-benzoyl adenosine 2-7 was prepared. The intermediates 2-12 and 2-7 were coupled with acetonitrile and 1H-tetrazole, and trivalent phosphorus was oxidized to produce 2-13 in the yield of 89.3ON- / 5- deprotection, purification, in situ intramolecular cyclization under the action of 1H-tetrazole and bis (diisopropylamino) 2-cyanoethoxy) phosphine. After oxidation, the compound 2-14 was synthesized in 80% yield, and then the protective group was removed to obtain the target compound 2CGAMP. In the second part of the work, the intermediate 2-10 was used as the raw material, Reaction with phosphorous acylation reagent to produce phosphorous amide intermediate 2- tert-Ding Ji dimethylsilane -3- [2-cyano-ethoxy -N- N- N-diisopropylamino] -5- dimethoxytriphenylmethyl-N2-isobutoxy guanosine 3-1, the intermediates 3-1 and 2-7 in acetonitrile and diisopropyl amino acid, the intermediates 3-1 and 2-7 in acetonitrile and acetonitrile. 1H-Tetrazole is coupled by the action of 1 H-Tetrazole, The yield after oxidation is 95%. After 3% -5% deprotection and in situ intramolecular cyclization, the oxidation yield is 86%. Finally, the target compound 3CGAMP is obtained by deprotection. In the third part of the work, the intermediate 2-5 is used as the raw material, Reaction with phosphorous acylation reagent to produce phosphorous amide intermediate 2- tert-Ding Ji dimethylsilane -3- [2-cyano-ethoxy -N- N- N-diisopropylamino] -5PHOXYDIMETHYL 4-1, intermediates 4-1 and 2-7 in acetonitrile and diisopropyl amino group, 4-1 and 2-7 in acetonitrile and diisopropyl amino acid, 4-1 and 2-7 in acetonitrile and diisopropyl amino group respectively, and the intermediate 4-1 and 2-7 in acetonitrile and acetonitrile. 1H-Tetrazole coupling, The yield of cyclized chain dinucleoside monophosphoric acid was 83% after oxidation and purification. After removing the protective group, the target compound 3C- di-AMP3 was obtained.
【學位授予單位】：河南師范大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914

【參考文獻】

相關(guān)期刊論文 前2條

1 那路新;楊振軍;;環(huán)二鳥苷酸(c-di-GMP)在微生物體內(nèi)的作用及其類似物的研究[J];藥學學報;2012年03期

2 王錦華,陳奎生,張云漢,羅偉;cAMP類似物對人乳腺癌細胞cyclinD1表達的影響[J];安徽醫(yī)藥;2003年06期

，

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