万古霉素动态组合化学研究
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摘要
万古霉素是一种糖肽抗菌素,是人类用来抵抗革兰氏阳性细菌感染的最后一道防线。万古霉素的抑菌机理之一是通过其七肽骨架与细菌细胞壁糖蛋白合成启动子——胞壁酰五肽的末端二肽片段D-Ala-D-Ala形成五个氢键来抑制细菌细胞壁的生长,从而导致细菌细胞凋亡。近年来,万古霉素的过度使用导致了耐药菌的出现,即细菌细胞壁合成启动子的末端由D-Ala-D-Ala突变成D-Ala-D-Lac。
动态组合化学是一种新兴的组合化学技术,是通过物理与化学的动态变化、集合成与筛选为一体的组合化学研究方法。其特点是在物理非共价结合为驱动的条件下,进行动力学稳态化学反应,并将这种化学反应识别出来,进而发现分子间相互作用的内容和形式。基于固相筛选具有易分离、操作简便、适合于筛选大数量化合物等特点,本文建立了固载化探针筛选动态组合化学库的方法,并对N-去甲万古霉素亮氨酸的氨基进行动态修饰,以寻找与D-Ala-D-Ala结合能力更强的新万古霉素类似物,具体为:
(一)以PEGA氨基树脂为载体,利用丁二酸酐将树脂上的反应官能团转化成羧基,采用叔丁酯保护策略以100%的效率逆向合成了C-端羧基裸露的PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2。采用高分辨魔角核磁共振(HR/MAS NMR)技术研究了PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2与N-去甲万古霉素之间的氢键作用。
(二)基于席夫碱(schiff-base)反应的可逆性,以及N-去甲万古霉素亮氨酸氨基反应活性高于糖片段氨基的特点,构建了N-去甲万古霉素亮氨酸氨基的席夫碱动态组合化学库。通过探针PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2的结合驱动作用筛选到一个新的万古霉素类似物cyy202。HR/MAS NMR研究和紫外差谱结合常数测定结果表明,该化合物与D-Ala-D-Ala之间的氢键作用是N-去甲万古霉素的2倍。
(三)为了与固载化探针筛选动态组合化学库策略进行对照,以游离的(Ac)_2-L-Lys-D-Ala-D-Ala-OH为探针,以N-去甲万古霉素为底物,本文构建并筛选了对应的液相动态组合化学库,发现了三种新化合物cyy202、cyy201及cyy209。结合常数测定结果表明后两者与探针的结合能力弱于N-去甲万古霉素。
综上所述,可以得到如下创新性结论:
1)固载化D-Ala-D-Ala二聚体PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2可以作为筛选N-去甲万古霉素动态组合化学库的探针。
2)固载化探针分子策略可以用于研究小分子与中等分子之间的动态相互作用,实现筛选动态组合化学库的目的。
3)固载化探针分子筛选策略的选择性高于液相筛选策略。
此外,依据本实验室前期研究工作的积累,本文进一步合成了万古霉素新类似物的糖片断氨基的芴甲氧羰酰基(Fmoc)化衍生物,其生物活性正在测试中。
最后,以(Ac)_2-L-Lys-D-Ala-D-Lac-OH为探针,以N-去甲万古霉素为底物初步筛选了其液相动态组合化学库,尚未发现潜在的活性化合物。该结果表明,寻找能够与D-Ala-D-Lac有强相互作用的万古霉素类似物难度更大,需要进一步扩大动态组合化学库的容量,以便增大发现能够与D-Ala-D-Lac有强相互作用的万古霉素类似物的机会。
Vancomycin is a glycopeptidic antibiotic enlisted as the last line of defense against methicilin-resistant Gram-positive infections. Vancomycin exerts its antibacterial action by binding to the terminal D-Ala-D-Ala fragment of the growing peptidoglycan biosynthetic precursor through an intricate network of five hydrogen bonds, thereby inhibiting cell wall growth and cross-linking. However, excessive usage of vancomycin has clinically mutanted the D-Ala-D-Ala of bacteria cell wall into the D-Ala-D-Lac which makes binding ability of vancomycin drop down 1000 times.
Dynamic combinatorial chemistry (DCC) makes use of reversible bond-forming reactions to create thermodynamically controlled library. Upon addition of a target molecule or a probe, the molar fractions of individual library member are perturbed as a function of their affinity to that target or probe. Solid-phase screening with the merits of easy separation and operation is benefit from the potential screening of large number compounds and quick determination of the interesting molecular structures and the interactions between them. This thesis aimed to develop a highly throughput resin-bound probe screening method by using a dynamic library of N-demethylvanco -mycin to find vancomycin analogues with better binding ability to the D-Ala-D-Ala in the DCL of amino group of N-demethylvancomycin's leucin residue.
1) Through the action of succinic anhydride the -NH_2 function of PEGA resin was converted into -COOH. The resin-bound probe PEGA-L-Lys(-Suc-D-Ala-D-Ala -OH)_2 then was obtained with 100% yield by t-butyl esters protective stratege of D-Alanine. The hydrogen-bound interactions between PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 and N-demethylvancomycin were studied by high resolution magic angle spinning NMR (HR/MAS NMR).
2) Through the screening actions of PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 a novel of vancomycin analog has been identified which is stronger binding to D-Ala-D-Ala as two times as N-demethylvancomycin by the U.V. difference spectroscopy evaluation.
3) In order to further validate and compare the solid-phase screening method, corresponding liquid-phase DCL was designed and screened in this thesis with free (Ac)_2-L-Lys-D-Ala-D-Ala-OH as probe. Same analog of vancomycin was also identified, however, with the lower selectivity.
In summary, 1) PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 is able to be used as probe to screening DCL of N-demethylvancomycine. 2) The resin-bound probe method is compatible with the study of the interactions between small molecules and middle molecules. 3) The solid-phase screening approach is more specific than liquid-phase method.
Based on our previous results, the vancosamine Fmoc derivatives of the new vancomycin analogues were also synthesized. Their antibacterial activity against various vancomycin sensitive and resistant strains is under testing.
Meaning while, screening the same vancomycin dynamic library by using free (Ac)_2-L-Lys-D-Ala-D-Lac-OH probe was also performed in this thesis. However, none of potential compounds was found. This result indicates that looking for the vancomycin analog with strong binding to D-Ala-D-Lac will be more difficult and lower chance. Increasing the library size could be necessary.
动态组合化学是一种新兴的组合化学技术,是通过物理与化学的动态变化、集合成与筛选为一体的组合化学研究方法。其特点是在物理非共价结合为驱动的条件下,进行动力学稳态化学反应,并将这种化学反应识别出来,进而发现分子间相互作用的内容和形式。基于固相筛选具有易分离、操作简便、适合于筛选大数量化合物等特点,本文建立了固载化探针筛选动态组合化学库的方法,并对N-去甲万古霉素亮氨酸的氨基进行动态修饰,以寻找与D-Ala-D-Ala结合能力更强的新万古霉素类似物,具体为:
(一)以PEGA氨基树脂为载体,利用丁二酸酐将树脂上的反应官能团转化成羧基,采用叔丁酯保护策略以100%的效率逆向合成了C-端羧基裸露的PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2。采用高分辨魔角核磁共振(HR/MAS NMR)技术研究了PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2与N-去甲万古霉素之间的氢键作用。
(二)基于席夫碱(schiff-base)反应的可逆性,以及N-去甲万古霉素亮氨酸氨基反应活性高于糖片段氨基的特点,构建了N-去甲万古霉素亮氨酸氨基的席夫碱动态组合化学库。通过探针PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2的结合驱动作用筛选到一个新的万古霉素类似物cyy202。HR/MAS NMR研究和紫外差谱结合常数测定结果表明,该化合物与D-Ala-D-Ala之间的氢键作用是N-去甲万古霉素的2倍。
(三)为了与固载化探针筛选动态组合化学库策略进行对照,以游离的(Ac)_2-L-Lys-D-Ala-D-Ala-OH为探针,以N-去甲万古霉素为底物,本文构建并筛选了对应的液相动态组合化学库,发现了三种新化合物cyy202、cyy201及cyy209。结合常数测定结果表明后两者与探针的结合能力弱于N-去甲万古霉素。
综上所述,可以得到如下创新性结论:
1)固载化D-Ala-D-Ala二聚体PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2可以作为筛选N-去甲万古霉素动态组合化学库的探针。
2)固载化探针分子策略可以用于研究小分子与中等分子之间的动态相互作用,实现筛选动态组合化学库的目的。
3)固载化探针分子筛选策略的选择性高于液相筛选策略。
此外,依据本实验室前期研究工作的积累,本文进一步合成了万古霉素新类似物的糖片断氨基的芴甲氧羰酰基(Fmoc)化衍生物,其生物活性正在测试中。
最后,以(Ac)_2-L-Lys-D-Ala-D-Lac-OH为探针,以N-去甲万古霉素为底物初步筛选了其液相动态组合化学库,尚未发现潜在的活性化合物。该结果表明,寻找能够与D-Ala-D-Lac有强相互作用的万古霉素类似物难度更大,需要进一步扩大动态组合化学库的容量,以便增大发现能够与D-Ala-D-Lac有强相互作用的万古霉素类似物的机会。
Vancomycin is a glycopeptidic antibiotic enlisted as the last line of defense against methicilin-resistant Gram-positive infections. Vancomycin exerts its antibacterial action by binding to the terminal D-Ala-D-Ala fragment of the growing peptidoglycan biosynthetic precursor through an intricate network of five hydrogen bonds, thereby inhibiting cell wall growth and cross-linking. However, excessive usage of vancomycin has clinically mutanted the D-Ala-D-Ala of bacteria cell wall into the D-Ala-D-Lac which makes binding ability of vancomycin drop down 1000 times.
Dynamic combinatorial chemistry (DCC) makes use of reversible bond-forming reactions to create thermodynamically controlled library. Upon addition of a target molecule or a probe, the molar fractions of individual library member are perturbed as a function of their affinity to that target or probe. Solid-phase screening with the merits of easy separation and operation is benefit from the potential screening of large number compounds and quick determination of the interesting molecular structures and the interactions between them. This thesis aimed to develop a highly throughput resin-bound probe screening method by using a dynamic library of N-demethylvanco -mycin to find vancomycin analogues with better binding ability to the D-Ala-D-Ala in the DCL of amino group of N-demethylvancomycin's leucin residue.
1) Through the action of succinic anhydride the -NH_2 function of PEGA resin was converted into -COOH. The resin-bound probe PEGA-L-Lys(-Suc-D-Ala-D-Ala -OH)_2 then was obtained with 100% yield by t-butyl esters protective stratege of D-Alanine. The hydrogen-bound interactions between PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 and N-demethylvancomycin were studied by high resolution magic angle spinning NMR (HR/MAS NMR).
2) Through the screening actions of PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 a novel of vancomycin analog has been identified which is stronger binding to D-Ala-D-Ala as two times as N-demethylvancomycin by the U.V. difference spectroscopy evaluation.
3) In order to further validate and compare the solid-phase screening method, corresponding liquid-phase DCL was designed and screened in this thesis with free (Ac)_2-L-Lys-D-Ala-D-Ala-OH as probe. Same analog of vancomycin was also identified, however, with the lower selectivity.
In summary, 1) PEGA-L-Lys(-Suc-D-Ala-D-Ala-OH)_2 is able to be used as probe to screening DCL of N-demethylvancomycine. 2) The resin-bound probe method is compatible with the study of the interactions between small molecules and middle molecules. 3) The solid-phase screening approach is more specific than liquid-phase method.
Based on our previous results, the vancosamine Fmoc derivatives of the new vancomycin analogues were also synthesized. Their antibacterial activity against various vancomycin sensitive and resistant strains is under testing.
Meaning while, screening the same vancomycin dynamic library by using free (Ac)_2-L-Lys-D-Ala-D-Lac-OH probe was also performed in this thesis. However, none of potential compounds was found. This result indicates that looking for the vancomycin analog with strong binding to D-Ala-D-Lac will be more difficult and lower chance. Increasing the library size could be necessary.
引文
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