Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities
Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities
复制标题
具有神经刺激活性的二聚叶秋碱类似物的设计和合成。
DOI：
10.1021/acschemneuro.6b00188
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发表时间：
2016-10-01
影响因子：
5
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
--
作者：
Tang, Genyun;Liu, Xin;Chen, Wei-Min
神经突的生长在神经元发育和再生过程中起着至关重要的作用，旨在促进神经突发生的策略有利于神经元变性和损伤后突触连接的重建。使用二价类似物策略作为一种成功的方法，目前的研究确定了一系列新的二聚物securinine类似物作为有效的神经突生长促进剂。化合物13、14、17-19和21-23在两个securinine分子的C-15位置上具有不同长度的N，N-二烷基取代二酸酰胺连接物，对神经元细胞的分化和神经突延伸均有显著的积极作用。化合物14是活性最强的化合物之一，作为机制研究的代表化合物。其对神经突生长的作用是通过磷酸化/激活多种信号分子，包括Ca2+/钙调素依赖性蛋白激酶II （CaMKII）、细胞外信号调节激酶（ERK）和Akt。这些发现共同确定了一组新的对神经新生有益的化合物，并可能为神经修复和再生的药物发现提供见解。
Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.