红霉素衍生物的设计、合成与抗菌活性研究
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摘要
红霉素A是目前临床上常用的大环内酯类抗生素，主要用于治疗由革兰氏阳性菌引起的呼吸道感染、性病、皮肤以及软组织感染等疾病。但是，其抗菌谱窄、生物利用度差以及胃肠道副反应等缺点限制了红霉素A的应用。八十年代末期问世的第二代大环内酯类抗生素克服了红霉素A对酸不稳定性的缺点，具有抗菌谱广、活性高、药代动力学性质良好、毒副作用小等特点，现已广泛用于临床，其代表药物包括克拉霉素和阿奇霉素等。但是，第二代大环内酯类抗生素与红霉素A一样，对大环内酯耐药菌活性较差。
目前，研究对大环内酯耐药菌有效的新型大环内酯类衍生物方面，取得重大进展，出现如酮内酯、酰内酯、4″-氨基甲酸酯和2，3-去氢内酯等新型红霉素衍生物。其中，酮内酯类代表药物泰利霉素已于2001年上市，对包括大环内酯耐药菌在内的革兰氏阳性菌显示良好抗菌活性，主要用于呼吸道感染的治疗；6-O-取代酮内酯衍生物Cethromycin的抗菌活性较泰利霉素更好，即将完成临床评价，并可能很快上市。
本论文的研究工作是以红霉素A和阿奇霉素为先导化合物，通过对红霉素A9-位酮羰基以及阿奇霉素3-位克拉定糖基和其侧链部分进行化学修饰和结构优化，共设计、合成了目标化合物65个，均为未见文献报道的新化合物。
首先，对阿奇霉素3-位克拉定糖基进行结构改造，通过脱3-位克拉定糖并利用DMAP为催化剂，DCC为缩水剂，进行3-位羟基酯化反应合成了阿奇霉素的酰内酯类衍生物F-1～F-8。
在合成阿奇霉素4″-氨基甲酸酯衍生物的过程中，通过增加1，1′-羰基二咪唑和无水碳酸钾的投料比例，合成了2′-O-乙酰基-9-脱氧-9α-氮杂-4″-O-(咪唑-1-甲酰基)-9α-甲基-9α-同型红霉素A11，12-环碳酸酯。参照文献合成方法，经2′-O-乙酰基-9-脱氧-9α-氮杂-4″-O-(咪唑-1-甲酰基)-9α-甲基-9α-同型红霉素A11，12-环碳酸酯与不同的伯胺反应合
Erythromycin A has been routinely used to treat upper and lower respiratory tract infections, as well as social disease, skin and soft issue infections caused by gram-positive bacteria. However, erythromycin is hindered by its poor bioavailability, limited spectrum of activity and frequent gastrointestinal side effects. To overcome erythromycin A's limitation, the second-generation macrolide antibiotics, Clarithromycin and Azithromycin, were developed in 1980s. They have enjoyed great clinical success due to their enhanced antibacterial activity, expanded spectrum of activity, improved pharmacokinetic properties and attenuated gastrointestinal side effects as compared to erythromycin. Unfortunately, like erythromycin A, the second-generation macrolide antibiotics have poor activity against macrolide-resistant bacteria.
Now, the intensive search for the third-generation macrolide antibiotics that overcome the problem of resistance have unveiled four classes of macrolides, termed ketolides, acylides, 4"-carbamates and 2,3-anhydrolides. Telithromycin, which is a ketolide representative and has come into market in 2000, shows good antibacterial activity against gram-positive macrolide-susceptive and -resistant organisms. It has fine acid-stability and is used in the treatment of respiratory tract infection. Cethromycin, which is a 6-O-substituated ketolide, shows improved antibacterial activity compared to Telithromycin and will come into market. These successes demonstrate that modifying the chemical structure of erythromycin is an important approach to finding novel macrolide antibiotics.
Erythromycin A and Azithromycin were identified as lead compounds in this paper.
目前，研究对大环内酯耐药菌有效的新型大环内酯类衍生物方面，取得重大进展，出现如酮内酯、酰内酯、4″-氨基甲酸酯和2，3-去氢内酯等新型红霉素衍生物。其中，酮内酯类代表药物泰利霉素已于2001年上市，对包括大环内酯耐药菌在内的革兰氏阳性菌显示良好抗菌活性，主要用于呼吸道感染的治疗；6-O-取代酮内酯衍生物Cethromycin的抗菌活性较泰利霉素更好，即将完成临床评价，并可能很快上市。
本论文的研究工作是以红霉素A和阿奇霉素为先导化合物，通过对红霉素A9-位酮羰基以及阿奇霉素3-位克拉定糖基和其侧链部分进行化学修饰和结构优化，共设计、合成了目标化合物65个，均为未见文献报道的新化合物。
首先，对阿奇霉素3-位克拉定糖基进行结构改造，通过脱3-位克拉定糖并利用DMAP为催化剂，DCC为缩水剂，进行3-位羟基酯化反应合成了阿奇霉素的酰内酯类衍生物F-1～F-8。
在合成阿奇霉素4″-氨基甲酸酯衍生物的过程中，通过增加1，1′-羰基二咪唑和无水碳酸钾的投料比例，合成了2′-O-乙酰基-9-脱氧-9α-氮杂-4″-O-(咪唑-1-甲酰基)-9α-甲基-9α-同型红霉素A11，12-环碳酸酯。参照文献合成方法，经2′-O-乙酰基-9-脱氧-9α-氮杂-4″-O-(咪唑-1-甲酰基)-9α-甲基-9α-同型红霉素A11，12-环碳酸酯与不同的伯胺反应合
Erythromycin A has been routinely used to treat upper and lower respiratory tract infections, as well as social disease, skin and soft issue infections caused by gram-positive bacteria. However, erythromycin is hindered by its poor bioavailability, limited spectrum of activity and frequent gastrointestinal side effects. To overcome erythromycin A's limitation, the second-generation macrolide antibiotics, Clarithromycin and Azithromycin, were developed in 1980s. They have enjoyed great clinical success due to their enhanced antibacterial activity, expanded spectrum of activity, improved pharmacokinetic properties and attenuated gastrointestinal side effects as compared to erythromycin. Unfortunately, like erythromycin A, the second-generation macrolide antibiotics have poor activity against macrolide-resistant bacteria.
Now, the intensive search for the third-generation macrolide antibiotics that overcome the problem of resistance have unveiled four classes of macrolides, termed ketolides, acylides, 4"-carbamates and 2,3-anhydrolides. Telithromycin, which is a ketolide representative and has come into market in 2000, shows good antibacterial activity against gram-positive macrolide-susceptive and -resistant organisms. It has fine acid-stability and is used in the treatment of respiratory tract infection. Cethromycin, which is a 6-O-substituated ketolide, shows improved antibacterial activity compared to Telithromycin and will come into market. These successes demonstrate that modifying the chemical structure of erythromycin is an important approach to finding novel macrolide antibiotics.
Erythromycin A and Azithromycin were identified as lead compounds in this paper.
引文
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