Synthesis and biological activity of phospholipase C-resistant analogues of phosphatidylinositol 4,5-bisphosphate.

Journal of the American Chemical Society
Honglu ZhangG D Prestwich

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.

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Citations

May 3, 2007·Pflügers Archiv : European journal of physiology·Péter Várnai, Tamas Balla
May 5, 2007·Pflügers Archiv : European journal of physiology·Tibor Rohacs, Bernd Nilius
Dec 22, 2009·Organic & Biomolecular Chemistry·Stuart J ConwayAndrew B Holmes
Sep 18, 2021·Chemistry : a European Journal·Solène MorandSamuel Couve-Bonnaire

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