Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE.
Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE.
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DOI：
10.1016/j.bmc.2013.12.058
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发表时间：
2014-02-15
影响因子：
3.5
通讯作者：
Sucheck SJ
中科院分区：
文献类型：
--
作者：
Veleti SK;Lindenberger JJ;Ronning DR;Sucheck SJ
广泛耐药结核病（XDR-TB）的出现使得需要确定新的抗结核药物靶点以及更好地了解重要的生物合成途径。 GlgE 是结核分枝杆菌 (Mtb) 编码的麦芽糖基转移酶，参与 α-葡聚糖生物合成。 Mtb 中 GlgE 的缺失会导致细胞内 M1P 的积累，从而导致生物体快速死亡。为了抑制 GlgE，麦芽糖-C-膦酸酯 (MCP) 13 被设计为 M1P 的等排不可水解模拟物。 MCP 13 是唯一已知的 Mtb GlgE 抑制剂，是使用 Wittig 烯化作为将麦芽糖转化为所需产品的关键步骤成功合成的。 MCP 13 抑制 Mtb GlgE，IC50 = 230 ± 24 μM，使用测量正磷酸盐释放的偶联酶测定法测定。由于检测需要 M1P，因此有必要开发一种从 MCP 13 合成中使用的中间体到 M1P 的快速合成路线。总之，我们设计了 M1P 的底物类似物，它是第一个表现出 Mtb GlgE 抑制作用的。
The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. GlgE is a Mycobacterium tuberculosis (Mtb) encoded maltosyltransferase involved in α-glucan biosynthesis. Deletion of GlgE in Mtb results in the accumulation of M1P within cells leading to rapid death of the organism. To inhibit GlgE a maltose-C-phosphonate (MCP) 13 was designed to act as an isosteric non-hydrolysable mimic of M1P. MCP 13, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step in transforming maltose to the desired product. MCP 13 inhibited Mtb GlgE with an IC50 = 230 ± 24 μM determined using a coupled enzyme assay which measures orthophosphate release. The requirement of M1P for the assay necessitated the development of an expedited synthetic route to M1P from an intermediate used in the MCP 13 synthesis. In conclusion, we designed a substrate analogue of M1P that is the first to exhibit Mtb GlgE inhibition.
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影响因子：
4.3
作者：
Kolympadi, Maria;Fontanella, Marco;Vogel, Pierre
通讯作者：
Vogel, Pierre
DOI：
10.1073/pnas.89.11.4884
发表时间：
1992-06-01
影响因子：
11.1
作者：
WEBB, MR
通讯作者：
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影响因子：
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影响因子：
3.6
作者：
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通讯作者：
SAMUELSSON, B
影响因子：
1
作者：
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通讯作者：
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