具有5-位二甲基胺糖結(jié)構(gòu)修飾的十四元酮內(nèi)酯衍生物的合成及構(gòu)效關(guān)系研究
發(fā)布時(shí)間：2018-08-17 11:23
【摘要】：大環(huán)內(nèi)酯類抗生素具有抗菌譜寬、臨床服用方便、使用安全、毒副作用小等優(yōu)點(diǎn),多年來廣泛應(yīng)用于臨床上治療感染性疾病的治療。細(xì)菌對(duì)大環(huán)內(nèi)酯抗生素耐藥的問題日益嚴(yán)重,尤其是近年來,有關(guān)大環(huán)內(nèi)酯類抗生素耐藥菌株的報(bào)道不斷增多,這引起了研究人員的廣泛關(guān)注。 C-5位二甲基胺糖是大環(huán)內(nèi)酯發(fā)揮抗菌活性的最重要的官能團(tuán)。作為與細(xì)菌核糖體結(jié)合能的主要來源,對(duì)它進(jìn)行一定的結(jié)構(gòu)改造會(huì)引起抗菌活性的不同變化,這有助于我們從不同的角度來進(jìn)一步理解大環(huán)內(nèi)酯與靶點(diǎn)的作用機(jī)制從而找到有效抑制耐藥菌的化學(xué)結(jié)構(gòu)。 十六元大環(huán)內(nèi)酯在C-5位連有二糖結(jié)構(gòu),即在二甲基胺糖的4’-位還連有一個(gè)碳霉糖。與細(xì)菌核糖體作用的過程中,該二糖的伸展方向和十四元大環(huán)內(nèi)酯的C-5二甲基胺糖是一樣的,但是,碳霉糖能夠深入到肽酰轉(zhuǎn)移酶中心(PTC),直接抑制肽鍵的生成。而十四元大環(huán)內(nèi)酯中C-5位只有一個(gè)較短的單糖鏈,因此不能直接抑制肽鍵的生成,而是阻斷肽鏈的延長。 借鑒十六元大環(huán)內(nèi)酯的結(jié)構(gòu)特點(diǎn),對(duì)十四元大環(huán)內(nèi)酯的C-4'位進(jìn)行結(jié)構(gòu)修飾,通過在C-4'位引入不同結(jié)構(gòu)的側(cè)鏈(芳香或烷基側(cè)鏈),它們能夠在大環(huán)內(nèi)酯與細(xì)菌核糖體相互作用的過程中產(chǎn)生不同的影響,從而影響抑菌活性。這也有助于我們更深入地理解C-5位二甲基胺糖與23S rRNA的具體結(jié)合機(jī)制。 本論文研究思路具有很強(qiáng)的原創(chuàng)性,不僅可以豐富大環(huán)內(nèi)酯類化合物的結(jié)構(gòu)類型,而且對(duì)于大環(huán)內(nèi)酯與細(xì)菌核糖體具體作用機(jī)制的理解也大有裨益。 一、十四元大環(huán)內(nèi)酯4’-位進(jìn)行結(jié)構(gòu)改造的方法的構(gòu)建 采用匯聚式合成策略,分別以a-D-葡萄糖甲基苷為原料,通過9步線性反應(yīng),制備得到4-OBn保護(hù)的非天然二甲胺糖中間體；以克拉霉素為原料,經(jīng)過9步線性反應(yīng),制備得到了5-OH的紅霉內(nèi)酯糖受體。將糖供體與大環(huán)內(nèi)酯受體以較高的收率成功地進(jìn)行了偶連,并在此基礎(chǔ)上對(duì)4’-位進(jìn)行結(jié)構(gòu)衍生化。 二、十四元大環(huán)內(nèi)酯4’-位衍生物的合成和構(gòu)效關(guān)系研究 在將大環(huán)內(nèi)酯5-OH受體與非天然二甲胺糖供體成功偶連后,對(duì)4’-位進(jìn)行了三個(gè)系列的衍生：4’-位胺基甲酸酯類衍生物,4’-位酰胺類衍生物,4’-位芳香烷胺類衍生物。對(duì)得到的樣品化合物進(jìn)行了抗菌活性篩選,并研究分析其構(gòu)效關(guān)系,總結(jié)出了一些有助于加強(qiáng)大環(huán)內(nèi)酯與靶點(diǎn)結(jié)合作用的結(jié)構(gòu)特征。 三、十四元大環(huán)內(nèi)酯的3-OH的糖基化問題研究 鑒于二甲胺糖在大環(huán)內(nèi)酯結(jié)構(gòu)中的重要性及大環(huán)內(nèi)酯分子結(jié)構(gòu)的對(duì)稱性,嘗試將二甲胺糖與大環(huán)內(nèi)酯的3-OH進(jìn)行偶連反應(yīng),盡管最終沒有成功,卻加深了我們對(duì)各種不同的端基活性方法及偶連方法的理解和應(yīng)用能力�？偨Y(jié)了大環(huán)內(nèi)酯的3-OH糖基化反應(yīng)。
[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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5
本文編號(hào)：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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5
【共引文獻(xiàn)】
相關(guān)期刊論文 前4條
1 李豐;李宗耀;魏靈朝;張建平;蔣元力;;Pd/NaY催化苯甲醇無溶劑選擇性氧化反應(yīng)[J];工業(yè)催化;2014年07期
2 孫輝;周偉澄;;抗感染藥物研究進(jìn)展[J];藥學(xué)進(jìn)展;2013年08期
3 余劍;趙建寧;;破骨細(xì)胞活化過程中免疫內(nèi)酯LY267108對(duì)核因子κB的抑制[J];中國組織工程研究;2014年15期
4 靳龍龍;雷平生;;泰利霉素側(cè)鏈的合成[J];中國醫(yī)藥工業(yè)雜志;2014年07期
相關(guān)碩士學(xué)位論文 前8條
1 郭強(qiáng);泰拉霉素合成工藝研究[D];山東大學(xué);2013年
2 吳康年;阿奇霉素膠囊的臨床安全性試驗(yàn)及對(duì)犬的藥代動(dòng)力學(xué)研究[D];南京農(nóng)業(yè)大學(xué);2011年
3 單玲星;含芳基四氮唑烷基側(cè)鏈酰內(nèi)酯衍生物的合成與抗菌活性研究[D];暨南大學(xué);2013年
4 楊剛;NHPI對(duì)醇的選擇性氧化研究[D];大連工業(yè)大學(xué);2012年
5 趙英姿;大環(huán)內(nèi)酯類抗生素的酶活性抑制效應(yīng)及構(gòu)效關(guān)系研究[D];青島大學(xué);2014年
6 張俊賢;嗜熱真菌Thermomyces lanuginosusC5次生代謝產(chǎn)物的研究[D];云南大學(xué);2014年
7 靳龍龍;新結(jié)構(gòu)酮內(nèi)酯抗生素衍生物的合成及生物活性研究[D];北京協(xié)和醫(yī)學(xué)院;2014年
8 萬曉冉;地丹諾辛結(jié)晶工藝的研究及前藥修飾[D];華南理工大學(xué);2014年
，本文編號(hào)：2187473
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