Impairment of TNF-α production and action by imidazo[1,2-α] quinoxalines, a derivative family which displays potential anti-inflammatory properties
Impairment of TNF-α production and action by imidazo[1,2-α] quinoxalines, a derivative family which displays potential anti-inflammatory properties
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DOI：
10.1177/039463200601900308
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发表时间：
2006-07-01
影响因子：
3.5
通讯作者：
Dornand, J.
中科院分区：
文献类型：
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作者：
Morjaria, S.;Deleuze-Masquefa, C.;Dornand, J.
在以前的研究中，我们分析了一系列咪唑并[1，2-a]喹喔啉在我们的实验室设计的可能的咪喹莫特类似物的合成和性质。我们发现这些咪唑并[2-a]喹喔啉实际上是磷酸二酯酶4（PDE 4）的有效抑制剂。PDE 4抑制通常导致细胞内cAMP的增加，其在PBMC中诱导TNF-α mRNA转录的抑制，从而诱导细胞因子合成。这种作用与咪喹莫特的作用相反。此外，一些TNF-α诱导的活性，如依赖于细胞内cAMP水平的细胞凋亡也可能受到影响。因此，通过抵消TNF-α的性质和/或其产生，咪唑并[1，2-a]喹喔啉类可被认为是潜在的抗炎药物。本研究旨在证实或反驳这一假设。为此，我们表征了咪唑并[1，2-a]喹喔啉类化合物对TNF-α活性和合成的影响，以及它们作为PDE 4（IPDE 4）抑制剂的能力。我们发现咪唑并[1，2-a]喹喔啉类药物剂量依赖性地阻止TNF-α触发的L929细胞死亡，其中8系列（R4中的-NHCH 3）最有效。此外，当使用7962 T细胞研究8系列对TNF-α产生的影响时，观察到这些化合物损害TCR：CD 3触发的TNF-α产生。结构活性分析表明，这些药物的性质并不符合其IPDE 4的性质。这促使进一步探索可能参与TNF-α作用和产生的其他信号传导机制，特别是p38 MAPK和PI 3 K通路。我们在这里证明，咪唑并[1，2-a]喹喔啉以不同的方式靶向这些通路：它们激活p38 MAPK通路，同时抑制PI 3 K通路。这种对细胞信号传导的影响可以解释咪唑并[1，2-a]喹喔啉对TNF-α的1）作用和2）产生的影响，这将这些药物定义为潜在的抗炎剂。
In a previous study, we analysed the synthesis and properties of a series of imidazo[1,2-a]quinoxalines designed in our laboratory as possible imiquimod analogues. We found that these imidazo[2-a]quinoxalines were in fact potent inhibitors of phosphodiesterase 4 enzymes (PDE4). PDE4 inhibition normally results in an increase in intracellular cAMP which, in PBMC, induces the suppression of TNF-alpha mRNA transcription and thus cytokine synthesis. Such an effect is antagonistic to that of imiquimod. Furthermore, some TNF-alpha-induced activity, such as cell apoptosis which is dependent on the intracellular cAMP levels might also be affected. Therefore, by counteracting the properties of TNF-alpha and/or its production, the imidazo[1,2-alquinoxalines could be considered as potential anti-inflammatory drugs. The present study was performed to confirm or refute this hypothesis. For this, we characterized the effects of imidazo[1,2-a]quinoxalines both on TNF-alpha activity and synthesis in regard to their ability to act as inhibitors of PDE4 (IPDE4). We found that the imidazo[1,2-a]quinoxalines dose-dependently prevented the TNF-alpha-triggered death of L929 cells, with the 8-series (-NHCH3 in R4) being the most potent. Moreover, when the effect of the 8-series on TNF-alpha production was investigated using 7962 T cells, it was observed that these compounds impaired the TCR:CD3-triggered TNF-alpha production. Structure-activity analysis revealed that these properties of the drugs did not coincide with their IPDE4 properties. This prompted further exploration into other signalling mechanisms possibly involved in TNF-alpha action and production, notably the p38 MAPK and the PI3K pathway. We demonstrate here that the imidazo[1,2-alquinoxalines targeted these pathways in a different way: they activated the p38 MAPK pathway whilst inhibiting the PI3K pathway. Such effects on cell signalling could account for the imidazo[1,2-a]quinoxalines effects on 1) action and 2) production of TNF-alpha, which define these drugs as potential anti-inflammatory agents.