Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A
Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A
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DOI：
10.1021/jm300783c
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发表时间：
2012-08-09
影响因子：
7.3
通讯作者：
Yu, Donghui
中科院分区：
文献类型：
--
作者：
LaMarche, Matthew J.;Leeds, Jennifer A.;Yu, Donghui
为提高其化学稳定性和理化性质，开展了抗菌次级代谢物硫莫uracin A(1)的合成研究。1的官能团修饰包括去除C2-C7侧链，衍生C84环氧化区，改变C44羟基苯基丙氨酸基序。所得衍生物的化学结构简化稳定，抑菌活性相对于1。该衍生物的简化结构和改进的有机溶解度有助于从发酵液中分离产量，并简化了该过程所涉及的程序。这些进步为持续的药物化学优化增加了材料供应，最终鉴定出2，这是1的结构简化和化学稳定的类似物，保留了有效的抗生素活性。
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.