N-邻羟苯基取代氨基酸衍生物的设计合成及抗菌活性研究
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摘要
1998年,美国Tufts大学McMurry等发现三氯生是通过阻断细菌的脂肪酸合成而杀灭细菌的,首次证明负责编码脂肪酸合成的烯酰基-ACP还原酶(简称ENR)的FabI基因是其实质的作用靶标。随后的大量实验证明,“邻羟苯基”、“卤代邻羟苯基”等,是三氯生及其类似物抑杀病原体特异性基因的关键结构,可作为设计抗生化合物分子的核心结构单元。
近年来研究发现,将氨基酸引入活性分子后,可以改变活性分子的性质,增强其对靶细胞的作用和选择性,还可增强药物对膜的透过性,提高生物利用度,因而被广泛地应用于药物的分子设计和产品开发。
本课题以“邻羟苯基”、“卤代邻羟苯基”为母核,设计、合成了一系列N-(2-羟基苯基)桥连氨基酸类化合物。根据桥键的不同,将化合物进行如下分类:
1.“邻羟苯基”、“卤代邻羟苯基”直接修饰的氨基酸类化合物以邻氨基苯酚和溴乙酸乙酯为起始原料,经N-烷基化反应后得到N-(2-羟基苯基)甘氨酸乙酯,然后在碱性条件下水解得到N-(2-羟基苯基)甘氨酸。同时,采用Ullmann反应,也可得到N-(2-羟基苯基)甘氨酸和N-(2-羟基苯基)缬氨酸,验证了氨基酸在Cu+的催化下加速了Ullmann反应。
2.亚甲基为桥基的“邻羟苯基”、“卤代邻羟苯基”修饰氨基酸类化合物氨基酸和水杨醛先发生席夫碱缩合反应,经NaBH4还原后得到一系列的邻羟苄基氨基酸类化合物。将水杨醛溴化得到溴代的邻羟苄基氨基酸类化合物。通过对比反应揭示了水杨醛、溴代水杨醛与氨基酸反应的基本规律。在反应过程中,带有疏水性脂肪R基的氨基酸与水杨醛反应的速率较带有极性R基的氨基酸快;R基空间位阻越小,反应速率越快,其中,甘氨酸与水杨醛的反应速率最快。同时,单溴代后的席夫碱缩合反应更容易进行,二溴代时该效应更加明显,且伴随有收率增加的结果。
3.甲酰胺基为桥基的“邻羟苯基”、“卤代邻羟苯基”修饰氨基酸化合物以水杨酸甲酯为起始原料,经过肼解、N-烷基化反应得到N-(2-羟基苯甲酰胺基)甘氨酸乙酯,经碱性水解得到N-(2-羟基苯甲酰胺基)甘氨酸。
本文重点阐述了上述化合物的合成,研究了各类反应的影响因素及工艺条件,并探讨了一些反应的基本规律,推测了相关的反应机理。
同时,本文对合成的大部分化合物进行了抑菌活性的测试,总结了抑菌活性和化合物结构之间的关系。
In 1998, McMurry from American Tufts University discovered that triclosan killed the bacterium by blocking the synthesis of fatty acid, which proved that the FabI gene of acyl-ACP reductive enzyme (ENR) was the essential target for the first time. A lot of experiments were done afterward, which indicated that“2-hydroxyphenyl, 2-hydroxy-halophenyl”were the key structures of triclosan and its analogues that can kill the pathogenic germs. So“2-hydroxyphenyl, 2-hydroxy-halophenyl”were thought to be the core unit of antibiotic structure design.
According to the recent studies, active units can change their molecular properties、boost up their effects and selectivities to the target cell after linking amino acids, and this kind of structures also have a stronger permeance to the films and a higher biological usage. So this work is wildly applied in the drug molecule design and synthesis research.
A series of N-(2-hydroxyphenyl)-amino acids derivatives were designed and synthesized based on the key unit of“2-hydroxyphenyl, 2-hydroxy-halophenyl”.
1.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids directly N-(2-hydroxyphenyl)-glycine ethyl ester was obtained from 2-amino-phenol and bromo-acetic acid ethyl ester via N-alkylation, then the ester was hydrolyzed under the base condition to produce N-(2-hydroxyphenyl)-glycine. On the other hand, the above compounds also can be gained by Ullmann reaction, and the catalysis of amino acids with Cu+ was proved in this reaction.
2.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids with methylene Salicylaldehyde and halo-salicylaldehyde were condensed with amino acids in the presence of sodium hydroxide to obtain amino acids Schiff base, which were reduced by NaBH4 to produce N-(2-hydroxylbenzyl)-amino acids and N-(2-hydroxyl-halobenzyl)-amino acids respectively. The condensation reaction may be much faster if the amino acids have hydrophobic small R group rather than the hydrophilic and big ones, such as Gly.. The condensation reaction would be more active with the halo-salicylaldehyde, especially with the 3,5-dibromo-salicylaldehyde.
3.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids with N-methyl-acetamide [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid ethyl ester was obtained from 2-hydroxy-benzoic acid methyl ester via hydrazination and N-alkylation, then the ester was hydrolyzed to produce [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid.
Meanwhile, the antibacterial activities of most compounds were tested, and the relationships between antibacterial activities and structures also were discussed.
近年来研究发现,将氨基酸引入活性分子后,可以改变活性分子的性质,增强其对靶细胞的作用和选择性,还可增强药物对膜的透过性,提高生物利用度,因而被广泛地应用于药物的分子设计和产品开发。
本课题以“邻羟苯基”、“卤代邻羟苯基”为母核,设计、合成了一系列N-(2-羟基苯基)桥连氨基酸类化合物。根据桥键的不同,将化合物进行如下分类:
1.“邻羟苯基”、“卤代邻羟苯基”直接修饰的氨基酸类化合物以邻氨基苯酚和溴乙酸乙酯为起始原料,经N-烷基化反应后得到N-(2-羟基苯基)甘氨酸乙酯,然后在碱性条件下水解得到N-(2-羟基苯基)甘氨酸。同时,采用Ullmann反应,也可得到N-(2-羟基苯基)甘氨酸和N-(2-羟基苯基)缬氨酸,验证了氨基酸在Cu+的催化下加速了Ullmann反应。
2.亚甲基为桥基的“邻羟苯基”、“卤代邻羟苯基”修饰氨基酸类化合物氨基酸和水杨醛先发生席夫碱缩合反应,经NaBH4还原后得到一系列的邻羟苄基氨基酸类化合物。将水杨醛溴化得到溴代的邻羟苄基氨基酸类化合物。通过对比反应揭示了水杨醛、溴代水杨醛与氨基酸反应的基本规律。在反应过程中,带有疏水性脂肪R基的氨基酸与水杨醛反应的速率较带有极性R基的氨基酸快;R基空间位阻越小,反应速率越快,其中,甘氨酸与水杨醛的反应速率最快。同时,单溴代后的席夫碱缩合反应更容易进行,二溴代时该效应更加明显,且伴随有收率增加的结果。
3.甲酰胺基为桥基的“邻羟苯基”、“卤代邻羟苯基”修饰氨基酸化合物以水杨酸甲酯为起始原料,经过肼解、N-烷基化反应得到N-(2-羟基苯甲酰胺基)甘氨酸乙酯,经碱性水解得到N-(2-羟基苯甲酰胺基)甘氨酸。
本文重点阐述了上述化合物的合成,研究了各类反应的影响因素及工艺条件,并探讨了一些反应的基本规律,推测了相关的反应机理。
同时,本文对合成的大部分化合物进行了抑菌活性的测试,总结了抑菌活性和化合物结构之间的关系。
In 1998, McMurry from American Tufts University discovered that triclosan killed the bacterium by blocking the synthesis of fatty acid, which proved that the FabI gene of acyl-ACP reductive enzyme (ENR) was the essential target for the first time. A lot of experiments were done afterward, which indicated that“2-hydroxyphenyl, 2-hydroxy-halophenyl”were the key structures of triclosan and its analogues that can kill the pathogenic germs. So“2-hydroxyphenyl, 2-hydroxy-halophenyl”were thought to be the core unit of antibiotic structure design.
According to the recent studies, active units can change their molecular properties、boost up their effects and selectivities to the target cell after linking amino acids, and this kind of structures also have a stronger permeance to the films and a higher biological usage. So this work is wildly applied in the drug molecule design and synthesis research.
A series of N-(2-hydroxyphenyl)-amino acids derivatives were designed and synthesized based on the key unit of“2-hydroxyphenyl, 2-hydroxy-halophenyl”.
1.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids directly N-(2-hydroxyphenyl)-glycine ethyl ester was obtained from 2-amino-phenol and bromo-acetic acid ethyl ester via N-alkylation, then the ester was hydrolyzed under the base condition to produce N-(2-hydroxyphenyl)-glycine. On the other hand, the above compounds also can be gained by Ullmann reaction, and the catalysis of amino acids with Cu+ was proved in this reaction.
2.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids with methylene Salicylaldehyde and halo-salicylaldehyde were condensed with amino acids in the presence of sodium hydroxide to obtain amino acids Schiff base, which were reduced by NaBH4 to produce N-(2-hydroxylbenzyl)-amino acids and N-(2-hydroxyl-halobenzyl)-amino acids respectively. The condensation reaction may be much faster if the amino acids have hydrophobic small R group rather than the hydrophilic and big ones, such as Gly.. The condensation reaction would be more active with the halo-salicylaldehyde, especially with the 3,5-dibromo-salicylaldehyde.
3.“2-hydroxyphenyl, 2-hydroxy-halophenyl”linked amino acids with N-methyl-acetamide [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid ethyl ester was obtained from 2-hydroxy-benzoic acid methyl ester via hydrazination and N-alkylation, then the ester was hydrolyzed to produce [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid.
Meanwhile, the antibacterial activities of most compounds were tested, and the relationships between antibacterial activities and structures also were discussed.
引文
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