The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase
The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase
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DOI：
10.1039/b513409a
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Vederas, JC
中科院分区：
文献类型：
--
作者：
Diaper, CM;Sutherland, A;Vederas, JC
首次立体选择性地合成了二氨基庚二酸（DAP）的氮杂环丙烷类似物，并对其作为DAP差向异构酶抑制剂进行了评价。(2R，3S，3 ′ S）-3-合成了（3 '-氨基丙烷）氮丙啶-2，3'-二羧酸酯4，并显示其是DAP差向异构酶的可逆抑制剂，IC 50值为2.88 mM。（4-氨基-4-羧基丁基）氮丙啶-2-羧酸（LL-azi-DAP 14和DL-azi-DAP 29）被制备为纯的非对映异构体，并且两者均显示为DAP差向异构酶的不可逆抑制剂。LL-Azi-DAP 14选择性结合酶活性位点的Cys-73，而DL-azi-DAP 29通过巯基攻击抑制剂氮丙啶环的亚甲基而结合Cys-217。这些观察结果与提出的通过DAP差向异构酶使LL-DAP 1和meso-DAP 2差向异构化的两种基础机制一致。
Aziridine analogues of diaminopimelic acid (DAP) have been prepared stereoselectively for the first time and evaluated as inhibitors of DAP epimerase. (2R, 3S, 3'S)- 3-( 3'- Aminopropane)aziridine- 2,3'-dicarboxylate 4 was synthesised and shown to be a reversible inhibitor of DAP epimerase with an IC50 value of 2.88 mM. (2S, 4S)- and (2S, 4R)- 2-(4-Amino-4-carboxybutyl) aziridine-2-carboxylic acid ( LL-azi-DAP 14 and DL-azi-DAP 29) were made as pure diastereomers, and both were shown to be irreversible inhibitors of DAP epimerase. LL-Azi-DAP 14 selectively binds to Cys-73 of the enzyme active site whereas DL-azi-DAP 29 binds to Cys-217 via attack of sulfhydryl on the methylene of the inhibitor aziridine ring. These observations are consistent with the two base mechanism proposed for the epimerisation of LL-DAP 1 and meso-DAP 2 by DAP epimerase.