Total syntheses of mycobactin analogues as potent antimycobacterial agents using a minimal protecting group strategy
Total syntheses of mycobactin analogues as potent antimycobacterial agents using a minimal protecting group strategy
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DOI：
10.1021/jo980063o
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发表时间：
1998-06-26
影响因子：
3.6
通讯作者：
Miller, MJ
中科院分区：
文献类型：
--
作者：
Xu, YP;Miller, MJ
分枝杆菌素是由包括结核分枝杆菌在内的分枝杆菌生物合成的铁螯合剂（铁载体）家族，其作为生长促进剂。它们是重要的铁载体，由于其组分螯合官能团的化学性质，对Fe（III）具有高亲和力和特异性。母体化合物及其合成类似物可用于天然铁吸收机制的研究。Snow及其同事假设，替代和修饰的分枝杆菌素类似物可能作为分枝杆菌生长的拮抗剂，具有重要的治疗价值。四个不同的类似物的有效合成。使用水溶性碳二亚胺（EDC）可以显着改善酰胺键和酯键的形成。HCl）介导的偶联反应。使用HOAt超过其他传统偶联添加剂提供了所需偶联反应的反应速率的显著提高和最小化的副反应。通过在合成期间最小化保护基团的使用，使得进一步的简化成为可能。事实上，在游离异羟肟酸和游离酚羟基存在下的偶联组分以优异的产率进行。生物学研究表明，合成的类似物对M.结核病H37Rv.
Mycobactins are a family of iron sequestering agents (siderophores) biosynthesized as growth promoters by mycobacteria including Mycobacterium tuberculosis. They are important siderophores with high affinity and specificity for Fe(III) due to the chemical nature of their component chelating functional groups. The parent compounds and their synthetic analogues can be used for studies of natural iron uptake mechanisms. It was hypothesized by Snow and co-workers that alternate and modified mycobactin analogues might serve as antagonists of mycobacterial growth and be of important therapeutic value. Efficient syntheses of four different analogues are presented. Dramatic improvements on formation of amide and ester bonds were achieved using water soluble carbodiimide (EDC . HCl)-mediated couplings in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) as an additive. Using HOAt over other traditional coupling additives provided significant enhancement of the reaction rate of the desired coupling reactions and minimized side reactions. Further simplifications were made possible by minimizing the use of protecting groups during the syntheses. In fact, coupling components in the presence of free hydroxamic acids and a free phenolic hydroxyl group proceeded in excellent yields. Biological studies indicated that the resulting synthetic analogues effect moderate to high inhibition of the growth of M. tuberculosis H37Rv.