Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives.
Synthesis and monoamine oxidase B catalyzed oxidation of C-4 heteroaromatic substituted 1,2,3,6-tetrahydropyridine derivatives.
复制标题
C-4 杂芳族取代的 1,2,3,6-四氢吡啶衍生物的合成和单胺氧化酶 B 催化氧化。
DOI：
10.1021/tx960063o
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
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作者：
Nimkar,SK;Anderson,AH;Rimoldi,JM;Stanton,M;Castagnoli,KP;Mabic,S;Wang,YX;CastagnoliJr,N
单胺氧化酶B（MAO-B）催化的胺氧化反应主要通过极性途径、初始单电子转移途径和初始氢原子转移途径进行。先前对选定的N-环丙基-4-取代-1，2，3，6-四氢吡啶衍生物的研究结果使我们考虑了这些环状叔烯丙基胺的机制，其可能不一定涉及初始单电子转移步骤所需的胺基阳离子。本文总结的研究是为了进一步探索决定各种1，4-二取代四氢吡啶衍生物的MAO-B底物和/或灭活剂性质的结构特征。我们在这里报告的结果，我们的研究合成和单胺氧化酶-B催化氧化的1-甲基和1-环丙基-1，2，3，6-四氢吡啶衍生物轴承各种杂芳基在C-4。所有的N-环丙基四氢吡啶类似物都是MAO-B的时间和浓度依赖性抑制剂，而所有的N-甲基四氢吡啶类似物和N-环丙基-4-（1-甲基-2-吡咯基）四氢吡啶类似物都是底物。底物性质（kcat/KM）的范围为6至1800 min-1 mM-1，而可获得的kinact/KI值的灭活剂性质的范围为0.1−1.0 min-1 mM-1。除了4-（1-甲基-2-吡咯基）类似物的分配比为400之外，N-环丙基类似物的分配比在4至17之间变化。这些结果进行了讨论，在假定的烯丙基自由基中间体和氢原子转移和单电子转移为基础的机制的背景下。
The monoamine oxidase B (MAO-B) catalyzed oxidation of amines has been proposed to proceed via a polar pathway, an initial single-electron transfer pathway and an initial hydrogen atom transfer pathway. Results from previous studies on selectedN-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridine derivatives have led us to consider a mechanism for these cyclic tertiary allylamines which may not necessarily involve the aminyl radical cation as required by an initial single-electron transfer step. The studies summarized in this paper were undertaken to explore further the structural features that determine the MAO-B substrate and/or inactivator properties of various 1,4-disubstituted tetrahydropyridine derivatives. We report here the results of our studies on the synthesis and MAO-B catalyzed oxidation of 1-methyl- and 1-cyclopropyl-1,2,3,6-tetrahydropyridine derivatives bearing a variety of heteroaromatic groups at C-4. All of theN-cyclopropyltetrahydropyridine analogs were time and concentration dependent inhibitors of MAO-B while all of theN-methyltetrahydropyridine analogs and theN-cyclopropyl-4-(1-methyl-2-pyrryl)tetrahydropyridine analog were substrates. The substrate properties (kcat/KM) covered a range of 6 to 1800 min-1mM-1while the range for the inactivator properties for whichkinact/KIvalues could be obtained was 0.1−1.0 min-1mM-1. The partition ratios for theN-cyclopropyl analogs varied from 4 to 17 except for the 4-(1-methyl-2-pyrryl) analog, which had a partition ratio of 400. These results are discussed in terms of the putative allylic radical intermediate and in the context of the hydrogen atom transfer and single-electron transfer based mechanisms.