Potent Inhibition of Acid Sphingomyelinase by Phosphoinositide Analogues
Potent Inhibition of Acid Sphingomyelinase by Phosphoinositide Analogues
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磷酸肌醇类似物对酸性鞘磷脂酶的有效抑制
DOI：
10.1002/cbic.200900281
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发表时间：
2009
期刊：
影响因子：
3.2
通讯作者：
C. Arenz
中科院分区：
文献类型：
--
作者：
A. Roth;S. Redmer;C. Arenz
不同的哺乳动物鞘磷脂酶参与细胞调节、凋亡和炎症事件。最近的报告表明，药理潜力，特别是酸性鞘磷脂酶的抑制剂。磷脂酰肌醇-3，5二磷酸（PtdIns 3，5 P2）是迄今为止已知的最有效的选择性酸性鞘磷脂酶抑制剂。在本研究中，我们合成了PtdIns 3，5 P2的类似物，用于初步的构效关系（SAR）研究。我们鉴定了一种抑制剂，其易于合成，与PtdIns 3，5 P2相比具有上级化学和生物物理性质，并且应该对几乎所有磷脂酶稳定。最后但并非最不重要的是，新的抑制剂部分保护细胞免受地塞米松诱导的细胞死亡。
The different mammalian sphingomyelinases are involved in cell regulation, apoptosis and inflammatory events. Recent reports suggest pharmacological potential especially for inhibitors of the acid sphingomyelinase. Phosphatidyl inositol‐3,5bisphosphate (PtdIns3,5P2) is the most potent selective acid sphingomyelinase inhibitor known to date. In the present study, we synthesized analogues of PtdIns3,5P2 for initial structure–activity‐relationship (SAR) studies. We identified an inhibitor that is easy to synthesize, that has superior chemical and biophysical properties when compared to PtdIns3,5P2 and that should be stable against virtually all phospholipases. Last but not least, the new inhibitor partially protected cells from dexamethasone‐induced cell death.