Synthesis and biological activity of phospholipase C-resistant analogues of phosphatidylinositol 4,5-bisphosphate.
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.
Zhang
Honglu
H
Department of Medicinal Chemistry, University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
Xu
Yong
Y
Zhang
Zheng
Z
Liman
Emily R
ER
Prestwich
Glenn D
GD
D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000187:drug effects; D010738:Type C Phospholipases / Q000737:chemistry*
D019269:Phosphatidylinositol 4,5-Diphosphate; D050053:TRPM Cation Channels; D010738:Type C Phospholipases