磷脂酰肌醇4,5-二磷酸的磷脂酶C抗性类似物的合成及生物活性
Synthesis and biological activity of phospholipase C-resistant analogues of phosphatidylinositol 4,5-bisphosphate.
作者信息
Zhang Honglu, Xu Yong, Zhang Zheng, Liman Emily R, Prestwich Glenn D
机构信息
Department of Medicinal Chemistry, University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
出版信息
J Am Chem Soc. 2006 May 3;128(17):5642-3. doi: 10.1021/ja060621d.
Abstract
The membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is an important regulator in cell physiology. Hydrolysis of PtdIns(4,5)P2 by phospholipase C (PLC) releases two second messengers, Ins(1,4,5)P3 and diacylglycerol. To dissect the effects of PtdIns(4,5)P2 from those resulting from PLC-generated signals, a metabolically stabilized analogue of PtdIns(4,5)P2 was required. Two analogues were designed in which the scissile O-P bond was replaced with a C-P bond that could not be hydrolyzed by PLC activity. Herein we describe the asymmetric total synthesis of the first metabolically stabilized phospholipase C-resistant analogues of PtdIns(4,5)P2. The key transformation was a Pd(0)-catalyzed coupling of a H-phosphite with a vinyl bromide to form the desired C-P linkage. The phosphonate analogues of PtdIns(4,5)P2 were found to be effective in restoring the sensitivity of the TRPM4 channel to Ca2+ activation.
摘要
膜磷脂磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P2）是细胞生理学中的一种重要调节因子。磷脂酶C（PLC）对PtdIns(4,5)P2的水解会释放两种第二信使，即肌醇-1,4,5-三磷酸（Ins(1,4,5)P3）和二酰基甘油。为了区分PtdIns(4,5)P2的作用与PLC产生的信号所导致的作用，需要一种代谢稳定的PtdIns(4,5)P2类似物。设计了两种类似物，其中可裂解的O-P键被不能被PLC活性水解的C-P键取代。在此，我们描述了PtdIns(4,5)P2的首个代谢稳定的抗磷脂酶C类似物的不对称全合成。关键转化步骤是亚磷酸氢酯与溴化乙烯在钯(0)催化下偶联形成所需的C-P键。发现PtdIns(4,5)P2的膦酸酯类似物在恢复瞬时受体电位阳离子通道蛋白4（TRPM4）通道对Ca2+激活的敏感性方面是有效的。
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