具有5-位二甲基胺糖结构修饰的十四元酮内酯衍生物的合成及构效关系研究
发布时间：2018-08-17 11:23
【摘要】：大环内酯类抗生素具有抗菌谱宽、临床服用方便、使用安全、毒副作用小等优点,多年来广泛应用于临床上治疗感染性疾病的治疗。细菌对大环内酯抗生素耐药的问题日益严重,尤其是近年来,有关大环内酯类抗生素耐药菌株的报道不断增多,这引起了研究人员的广泛关注。 C-5位二甲基胺糖是大环内酯发挥抗菌活性的最重要的官能团。作为与细菌核糖体结合能的主要来源,对它进行一定的结构改造会引起抗菌活性的不同变化,这有助于我们从不同的角度来进一步理解大环内酯与靶点的作用机制从而找到有效抑制耐药菌的化学结构。 十六元大环内酯在C-5位连有二糖结构,即在二甲基胺糖的4’-位还连有一个碳霉糖。与细菌核糖体作用的过程中,该二糖的伸展方向和十四元大环内酯的C-5二甲基胺糖是一样的,但是,碳霉糖能够深入到肽酰转移酶中心(PTC),直接抑制肽键的生成。而十四元大环内酯中C-5位只有一个较短的单糖链,因此不能直接抑制肽键的生成,而是阻断肽链的延长。 借鉴十六元大环内酯的结构特点,对十四元大环内酯的C-4'位进行结构修饰,通过在C-4'位引入不同结构的侧链(芳香或烷基侧链),它们能够在大环内酯与细菌核糖体相互作用的过程中产生不同的影响,从而影响抑菌活性。这也有助于我们更深入地理解C-5位二甲基胺糖与23S rRNA的具体结合机制。 本论文研究思路具有很强的原创性,不仅可以丰富大环内酯类化合物的结构类型,而且对于大环内酯与细菌核糖体具体作用机制的理解也大有裨益。 一、十四元大环内酯4’-位进行结构改造的方法的构建 采用汇聚式合成策略,分别以a-D-葡萄糖甲基苷为原料,通过9步线性反应,制备得到4-OBn保护的非天然二甲胺糖中间体；以克拉霉素为原料,经过9步线性反应,制备得到了5-OH的红霉内酯糖受体。将糖供体与大环内酯受体以较高的收率成功地进行了偶连,并在此基础上对4’-位进行结构衍生化。 二、十四元大环内酯4’-位衍生物的合成和构效关系研究 在将大环内酯5-OH受体与非天然二甲胺糖供体成功偶连后,对4’-位进行了三个系列的衍生：4’-位胺基甲酸酯类衍生物,4’-位酰胺类衍生物,4’-位芳香烷胺类衍生物。对得到的样品化合物进行了抗菌活性筛选,并研究分析其构效关系,总结出了一些有助于加强大环内酯与靶点结合作用的结构特征。 三、十四元大环内酯的3-OH的糖基化问题研究 鉴于二甲胺糖在大环内酯结构中的重要性及大环内酯分子结构的对称性,尝试将二甲胺糖与大环内酯的3-OH进行偶连反应,尽管最终没有成功,却加深了我们对各种不同的端基活性方法及偶连方法的理解和应用能力。总结了大环内酯的3-OH糖基化反应。
[Abstract]:Macrolides have been widely used in the treatment of infectious diseases for many years due to their advantages of wide antibacterial spectrum, convenient clinical use, safe use, and low toxicity and side effects. The problem of bacterial resistance to macrolide antibiotics is becoming more and more serious, especially in recent years, the reports of macrolide antibiotic resistant strains have been increasing. C-5 dimethyl amines are the most important functional groups of macrolides for their antimicrobial activity. As the main source of ribosomal binding energy to bacteria, the modification of its structure will cause different changes in antibacterial activity. This will help us to further understand the mechanism of macrolide interaction with the target from different angles, and find out the chemical structure of drug resistant bacteria. The hexadecimal macrolide has a disaccharide structure at C-5 position and a carbamose at the 4 ~ (-) position of dimethyl aminosaccharide. In the process of interaction with bacterial ribosomes, the extended direction of the disaccharide is the same as that of C-5 dimethyl amines of 14-member macrolides. However, carbamose can directly inhibit the formation of peptide bonds into the (PTC), center of peptidyl transferase. However, the C-5 position of 14-member macrolides has only one short monosaccharide chain, so it can not directly inhibit the formation of peptide bond, but block the prolongation of peptide chain. Using the structural characteristics of hexadecyclic lactones for reference, the C-4 'site of 14-member macrolides was modified. By introducing different side chains (aromatic or alkyl side chains) at the C-4 'site, they have different effects on the interaction of macrolides with ribosomes, thus affecting bacteriostatic activity. It also helps us to understand the binding mechanism of C-5 dimethyl amines to 23s rRNA. The idea of this paper is very original, which can not only enrich the structural types of macrolides, but also help to understand the mechanism of the interaction between macrolides and bacterial ribosomes. Construction of a method for structural modification of monocyclic macrolides at the 4N site using convergent synthesis strategy, using a-D- glucomethyl glucoside as raw material, nine steps of linear reaction were used for the synthesis of a-D- glucomethyl glucoside. The unnatural dimethylaminose intermediate protected by 4-OBn was prepared. Clarithromycin was used as the raw material and the erythroid lactone receptor of 5-OH was prepared by 9 steps linear reaction. The sugar donor and macrolide receptor were successfully coupled with each other in high yield. Studies on the Synthesis and Structure-activity relationship of Derivatives of macrolides 4- and 4-, after successfully coupling the macrolide 5-OH receptor with the non-natural dimethylamine donor, In this paper, three series of derivatives of 4: 4-aminoformic acid esters have been carried out for the 4 ~ (th) ~ (-) Amido _ (4) Amido _ (4). The antimicrobial activity of the obtained compounds was screened and their structure-activity relationships were studied and analyzed. Some structural characteristics which were helpful to enhance the binding of macrolides to the target were summarized. Study on the glycosylation of 3-OH of three and fourteen member macrolides in view of the importance of dimethylaminose in the structure of macrolides and the symmetry of the molecular structure of macrolides, an attempt was made to couple the dimethylamine sugar with the 3-OH of macrolides. Although unsuccessful in the end, it has deepened our understanding and application ability of various terminal group activity methods and coupling methods. The 3-OH glycosylation of macrolides was summarized.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5
本文编号：2187473
[Abstract]:Macrolides have been widely used in the treatment of infectious diseases for many years due to their advantages of wide antibacterial spectrum, convenient clinical use, safe use, and low toxicity and side effects. The problem of bacterial resistance to macrolide antibiotics is becoming more and more serious, especially in recent years, the reports of macrolide antibiotic resistant strains have been increasing. C-5 dimethyl amines are the most important functional groups of macrolides for their antimicrobial activity. As the main source of ribosomal binding energy to bacteria, the modification of its structure will cause different changes in antibacterial activity. This will help us to further understand the mechanism of macrolide interaction with the target from different angles, and find out the chemical structure of drug resistant bacteria. The hexadecimal macrolide has a disaccharide structure at C-5 position and a carbamose at the 4 ~ (-) position of dimethyl aminosaccharide. In the process of interaction with bacterial ribosomes, the extended direction of the disaccharide is the same as that of C-5 dimethyl amines of 14-member macrolides. However, carbamose can directly inhibit the formation of peptide bonds into the (PTC), center of peptidyl transferase. However, the C-5 position of 14-member macrolides has only one short monosaccharide chain, so it can not directly inhibit the formation of peptide bond, but block the prolongation of peptide chain. Using the structural characteristics of hexadecyclic lactones for reference, the C-4 'site of 14-member macrolides was modified. By introducing different side chains (aromatic or alkyl side chains) at the C-4 'site, they have different effects on the interaction of macrolides with ribosomes, thus affecting bacteriostatic activity. It also helps us to understand the binding mechanism of C-5 dimethyl amines to 23s rRNA. The idea of this paper is very original, which can not only enrich the structural types of macrolides, but also help to understand the mechanism of the interaction between macrolides and bacterial ribosomes. Construction of a method for structural modification of monocyclic macrolides at the 4N site using convergent synthesis strategy, using a-D- glucomethyl glucoside as raw material, nine steps of linear reaction were used for the synthesis of a-D- glucomethyl glucoside. The unnatural dimethylaminose intermediate protected by 4-OBn was prepared. Clarithromycin was used as the raw material and the erythroid lactone receptor of 5-OH was prepared by 9 steps linear reaction. The sugar donor and macrolide receptor were successfully coupled with each other in high yield. Studies on the Synthesis and Structure-activity relationship of Derivatives of macrolides 4- and 4-, after successfully coupling the macrolide 5-OH receptor with the non-natural dimethylamine donor, In this paper, three series of derivatives of 4: 4-aminoformic acid esters have been carried out for the 4 ~ (th) ~ (-) Amido _ (4) Amido _ (4). The antimicrobial activity of the obtained compounds was screened and their structure-activity relationships were studied and analyzed. Some structural characteristics which were helpful to enhance the binding of macrolides to the target were summarized. Study on the glycosylation of 3-OH of three and fourteen member macrolides in view of the importance of dimethylaminose in the structure of macrolides and the symmetry of the molecular structure of macrolides, an attempt was made to couple the dimethylamine sugar with the 3-OH of macrolides. Although unsuccessful in the end, it has deepened our understanding and application ability of various terminal group activity methods and coupling methods. The 3-OH glycosylation of macrolides was summarized.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5
【共引文献】
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