G0775是一种新型细菌信号肽酶(Ⅰ)抑制剂,其结构新颖,作用机制独特,对革兰氏阴性菌(鲍曼不动杆菌、大肠杆菌、肺炎克雷伯菌和铜绿假单胞菌)具有强大的抗菌活性,且对多重耐药和广泛耐药病原体敏感.本研究以甲基(4S,7S,10S)-26-苄氧基-10-[{[(苄氧基)羰基]甲基}氨基]-16-羟基-7-甲基-6,9-二氧代-5,8-二氮杂-1,2(1,3)-二苯环癸烷-4-羧酸甲酯(Ⅰ-40)为起始原料,经过催化氢化、亲核取代等反应得到中间体甲基(4S,7S,10S)-10-[{[(苄氧基)羰基]甲基}氨基]-16,26-双[2-(叔丁氧羰基氨基)乙氧基]-7-甲基-6,9-二氧代-5,8-二氮杂-1,2(1,3)-二苯环癸烷-4-羧酸甲酯(Ⅰ-22),然后经脱保护,与(S)-4-[(叔丁氧基羰基)氨基]-2-{ 2-[4-(叔丁基)苯基]-4-甲基嘧啶-5-甲酰氨基} 丁酸(T4)缩合,再经水解和缩合反应,最后经脱保护得到目标产物G0775.与文献报道路线相比,本方法的反应步骤少,总产率高(68.16％),操作更简便.采用1H NMR、13 C NMR和HR-MS(ESI-TOF)对分子结构进行了表征.
New Synthesis Method of New Antibacterial Drug G0775
G0775 is a novel bacterial signal peptidase(Ⅰ)inhibitor with a novel structure and a unique mechanism of action.It is effective against Gram-negative bacteria(Acinetobacter baumannii,Escherichia coli,Klebsiella pneumoniae,and Pseudomonas aeruginosa)have potent antibacterial activi-ty and are susceptible to multidrug-resistant and extensively drug-resistant pathogens.In this study,methyl(4S,7S,10S)-26-benzyloxy-10-((((benzyloxy)carbonyl)methyl)amino)-16-hydroxy-7-meth-yl-6,9-dioxo-5,8-diaza-1,2(1,3)-diphenylcyclodecane-4-carboxylate methyl ester(Ⅰ-40)was used as the starting material,after catalytic hydrogenation and nucleophilic substitutions,intermediate methyl(4S,7S,10S)-10-((((benzyloxy)carbonyl)methyl)amino)-16,26-bis(2-(tert-butoxycarbonylami-no)ethoxy)-7-methyl-6,9-dioxo-5,8-diaza-1,2(1,3)-diphenylcyclo-deca-ne-4-carboxylicacid methyl ester(Ⅰ-22)was obtained.Then deprotected,condensed with(S)-4-((tert-butoxycarbonyl)amino)-2-(2-(4-(tert-butyl)phenyl)-4-methylpyrimidine-5-carbox amino)butanoic acid(T4),hydrolyzed,condensed,and finally deprotected to obtain the target product G0775.Compared with the route repor-ted in literature,this method has fewer reaction steps,higher overall yield(68.16％),and easier op-eration.The molecular structures were characterized by 1H NMR,13C NMR and HR-MS(ESI-TOF).
gram-negative bacteriaG0775alomycinbacterial signal peptidase Ⅰsynthetic method
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