A trifluoromethyl analog of verbenachalcone promotes neurite outgrowth and cell proliferation of NeuroScreen-1 cells.
A trifluoromethyl analog of verbenachalcone promotes neurite outgrowth and cell proliferation of NeuroScreen-1 cells.
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马鞭草酮的三氟甲基类似物可促进 NeuroScreen-1 细胞的神经突生长和细胞增殖。
DOI：
10.1007/s10571-010-9563-3
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发表时间：
2011
影响因子：
4
通讯作者：
Ibeanu,Gordon
中科院分区：
文献类型：
--
作者：
Yeyeodu,Susan;Gilyazova,Nailya;Huh,EunYoung;Dandepally,SrinivasaR;Oldham,Carla;Williams,Alfred;Ibeanu,Gordon
过去的研究表明，植物和海洋来源的天然产物及其同源物增强中枢神经系统（CNS）的神经生长因子（NGF）等神经生长因子的作用。然而，氟取代在其构效关系（SAR）中的作用尚未得到探讨。我们合成了马鞭草查尔酮（VC）的三氟甲基类似物，马鞭草查尔酮是一种具有生物活性的天然化合物，以前显示出增强NGF活性。这种类似物，命名为C278，增强NeuroScreen-1™（NS-1）细胞（PC 12嗜铬细胞瘤细胞的亚克隆）的神经突生长和增殖。与单独用NGF处理的对照相比，C278在次优剂量的NGF存在下增加了神经突承载细胞的百分比。此外，根据我们观察到的细胞数量增加以及MTT还原和刃天青试验的代谢评估结果，C278在低血清和无血清细胞培养条件下刺激细胞生长。C278的加入部分恢复了丝裂原活化蛋白激酶激酶（MEK）抑制剂PD 98059和U 0126对NGF诱导的神经突生长的抑制作用。与仅用MEK抑制剂和NGF处理的细胞相比，短期连续暴露于U 0126、C278和NGF的细胞增强了细胞外信号调节激酶（ERK）的磷酸化。C278还减弱了由暴露于PD 98059、U 0126和磷脂酰肌醇-3激酶（PI 3 K）抑制剂LY 294002引起的细胞生长停滞，但不改变Akt的磷酸化，Akt是细胞存活期间PI 3 K的经典下游靶点。这些数据表明，C278促进神经生长因子依赖的神经突起生长NS-1细胞通过MEK信号通路的机制，改变短期激活的ERK。相反，C278促进PI 3 K介导的生存独立于Akt磷酸化。
Past research has shown that natural products of plant and marine origins and their congeners enhance the actions of neuritogenic factors of the central nervous system (CNS) such as nerve growth factor (NGF). However, the role of fluorine substitutions in their structure–activity relationship (SAR) has not been explored. We have synthesized a trifluoromethyl analog of verbenachalcone (VC), a pharmacologically active natural compound previously shown to potentiate NGF activity. This analog, designated C278, enhances neurite outgrowth and proliferation of NeuroScreen-1™ (NS-1) cells, a subclone of PC12 pheochromocytoma cells. C278 increases the percentage of neurite bearing cells in the presence of suboptimal doses of NGF in comparison with controls treated with NGF alone. In addition, C278 stimulates cell growth in reduced serum and serum-free cell culture conditions based on our observation of increases in cell number and metabolic assessment with MTT reduction and resazurin assays. The addition of C278 partially restored inhibition of NGF-induced neurite outgrowth by the mitogen-activated protein kinase kinase (MEK) inhibitors PD98059 and U0126. Short-term sequential exposure of cells to U0126, C278, and NGF enhanced phosphorylation of extracellular signal-regulated kinase (ERK) in comparison with cells treated with only the MEK inhibitor and NGF. C278 also attenuated cell growth arrest caused by exposure to PD98059, U0126 and the phosphatidylinositol-3 kinase (PI3K) inhibitor, LY294002 but did not alter phosphorylation of Akt, a classic downstream target of PI3K during cell survival. These data suggest that C278 promotes NGF-dependent neurite outgrowth in NS-1 cells through a MEK signaling pathway by a mechanism that alters short-term activation of ERK. In contrast, C278 promotes PI3K-mediated survival independently of Akt phosphorylation.