基于靶向STING的环二核苷酸合成研究

发布时间：2018-05-27 11:00

本文选题：第二信使 + 环二核苷酸　；参考：《河南师范大学》2017年硕士论文

【摘要】：环二核苷酸是微生物的第二信使,在调节病原微生物的致病性和形态方面具有重要作用。环二核苷酸可被人体的免疫系统识别以抵抗病原微生物的进攻,而且能通过刺激肿瘤患者的免疫系统细胞产生细胞因子而杀伤肿瘤细胞。本论文提供了一种新的合成环二核苷酸类化合物的方法,该合成路线条件温和、操作简单、成本较低。本论文的工作主要包括以下三个部分:在第一部分的工作中,以鸟苷为原料,用三甲基氯硅烷对糖环上的羟基和鸟嘌呤上的氨基进行保护,然后用异丁酰氯选择性进攻氨基,再脱去三甲基硅基,得到N2-异丁酰基鸟苷。与DMTrC1反应,对5'-羟基进行保护;与TBDMSCl反应,对糖环上的3'-羟基进行保护;经过亚磷酰化反应,得到3'-叔丁基二甲基硅烷-2'-[(2-氰基乙氧基)-N,N-二异丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N2-异丁酰基鸟苷2-12。以腺苷为原料,与乙酸酐反应,对腺苷糖环上的2',3',5'-羟基进行保护;经过苯乙酰化反应,对腺嘌呤上的氨基进行保护,脱去乙酸酐,得到N6-苯甲酰基腺苷。用DMTrC1保护5'-羟基,TBDMSCl保护2'-羟基,乙酰丙酰基保护3'-羟基,随后脱去5'-羟基的保护基,制备了重要中间体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-苯甲酰基腺苷2-7。中间体2-12和2-7在乙腈和1H-四氮唑的作用下耦合,三价磷被氧化后生成2-13,收率是89%。3'-/5'-脱保护,纯化,在1H-四氮唑和双(二异丙基氨基)(2-氰基乙氧基)膦的作用下原位分子内环化,经氧化后生成化合物2-14,收率80%,再脱除保护基得到目标化合物2',3'-cGAMP。第二部分的工作中,以中间体2-10为原料,通过和亚磷酰化试剂反应生成亚磷酰胺中间体2'-叔丁基二甲基硅烷-3'-[(2-氰基乙氧基)-N,N-二异丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N2-异丁酰基鸟苷3-1,中间体3-1和2-7在乙腈和1H-四氮唑的作用下成耦合,氧化后的产率是95%,再经过3'-/5'-脱保护,原位分子内环化,氧化后收率是86%,再脱保护最终得到目标化合物3',3'-cGAMP。第三部分的工作中,以中间体2-5为原料,通过和亚磷酰化试剂反应生成亚磷酰胺中间体2'-叔丁基二甲基硅烷-3'-[(2-氰基乙氧基)-N,N-二异丙基氨基]-5'-(4,4'-二甲氧基三苯基甲基)-N6-苯甲酰基腺苷4-1,中间体4-1和2-7在乙腈和1H-四氮唑的作用下耦合,用环化试剂环化链状二核苷单磷酸,氧化和纯化后的产率为83%,脱除保护基团后得到目标化合物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.
【学位授予单位】：河南师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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