TAG-Assisted Liquid-Phase Synthesis and Structure Activity Relationship of Macolacin-Based Side-to-Tail Cyclopeptides Antibiotic  

作　　者：Haidi Li Yuankui Jin Minfan Pei Linyan Zhang Lianjun Wang Yuxin Yang Peng Xiang Taigang Liang 

机构地区：[1]Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology,Schoolof Pharmacy,Shanxi Medical University,Taiyuan,Shanxi 030001,China [2]Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University,Taiyuan,Shanxi 030001,China

出　　处：《Chinese Journal of Chemistry》2024年第22期2728-2742,共15页中国化学（英文版）

基　　金：supported by the Shanxi Provincial Key Research and Development Project(202102130501004).

摘　　要：TAG-assisted peptide synthesis technology enables optimal conservation of Fmoc amino acid raw materials and chemical solvents while eliminating the need for intricate chromatographic purification processes.This work presents a 4,4'-diphenylphosphonoxy diphenylcarbinol tag-mediated liquid-phase synthesis approach for preparing side-to-tail cyclopeptides macolacin which has strong activity against gram-negative bacteria,and its 15 analogues containing four N-methylation modified cyclopeptides,as well as an investigation of their structure-activity relationship(SAR).The synthesis of macolacin analogues primarily focuses on the modifications of the N-methylation group of Ile-7 and the tail fatty acyl chain of macolacin.The incorporation of N-methylation for Ile-7,along with the dihalogenated or monohalogenated benzoic acids for tail modification,exhibited remarkable antibacterial efficacy and minimal hepatocellular toxicity in vitro.The present study identified an N-methylation-modified antimicrobial cyclopeptide Ma14 that exhibits rapid bactericidal efficacy against A.baumanii,etc.,while showing reduced hepatocellular toxicity.Molecular docking simulations were conducted to investigate the binding of cyclopeptides to the outer membrane protein BamA of A.baumannii.The findings demonstrated the stable binding interactions of the cyclopeptides with the BamA protein and then presented a novel approach to explain the bacteriostatic mechanism of macolacin-based cyclopeptide antibiotics.

关 键 词：Macolacin N-Methylation-modified Cyclopeptide antibiotics Antimicrobial activity Structure-activity relationship TAG-assisted peptide synthesis Peptide Antimicrobial agents 

分 类 号：O62[理学—有机化学]