Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity
Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity
复制标题
2-Thr或10-Thr修饰的多粘菌素类似物的全合成和半合成，破译构效关系并提高抗菌活性
DOI：
10.1021/acs.jmedchem.0c02217
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发表时间：
2021
影响因子：
7.3
通讯作者：
Huang Wei
中科院分区：
文献类型：
--
作者：
Li Jian;Guan Dongliang;Chen Feifei;Shi Weiwei;Lan Lefu;Huang Wei
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 ofin vitroantibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity againstPseudomonas aeruginosabut had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound76exhibited 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.
