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Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity

文献类型：期刊论文

作者Li, Jian1,2,3; Guan, Dongliang1; Chen, Feifei4; Shi, Weiwei1,3; Lan, Lefu2,3,4; Huang, Wei1,2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-05-13
卷号64期号:9页码:5746-5765
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c02217
通讯作者Lan, Lefu(llan@simm.ac.cn) ; Huang, Wei(huangwei@simm.ac.cn)
英文摘要Herein, we report the total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure-activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification of 2-Thr or dual esterification of both 2- and 10-Thr. Based on the results of in vitro antibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity against Pseudomonas aeruginosa but had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound 76 exhibited 2-8-fold higher activity against different strains and lower toxicity toward the HK-2 cell line. This work explored the SAR of polymyxin 2-/10-Thr and provided a promising strategy for the development of novel polymyxin derivatives.
WOS关键词B NONAPEPTIDE ; LIPOPOLYSACCHARIDE ; DERIVATIVES ; ANTIBIOTICS ; BINDING ; SENSITIZATION ; PEPTIDES ; COLISTIN
资助项目National Natural Science Foundation of China (NSFC)[21877116] ; Shanghai Action Plan of Technological Innovation[18431900700] ; SIMM institute fund[CA-SIMM0120202009] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-006] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2019ZX09721001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000651785800031
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/297268]  
专题新药研究国家重点实验室
通讯作者Lan, Lefu; Huang, Wei
作者单位1.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
2.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Jian,Guan, Dongliang,Chen, Feifei,et al. Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(9):5746-5765.
APA Li, Jian,Guan, Dongliang,Chen, Feifei,Shi, Weiwei,Lan, Lefu,&Huang, Wei.(2021).Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity.JOURNAL OF MEDICINAL CHEMISTRY,64(9),5746-5765.
MLA Li, Jian,et al."Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity".JOURNAL OF MEDICINAL CHEMISTRY 64.9(2021):5746-5765.

入库方式： OAI收割

来源：上海药物研究所

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