183429-89-2Relevant academic research and scientific papers
Synthesis of phosphotriester analogues of the phosphoinositides PtdIns(4,5)P2 and PtdIns(3,4,5)P3
Gu, Qu-Ming,Prestwich, Glenn D.
, p. 8642 - 8647 (2007/10/03)
A synthetic route was developed for the preparation of novel O-(3-aminopropyl) tethered phosphotriester analogs (5) of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5,)P2, or PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3, or PIP3) using the coupling reagent 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite. The phosphotriester ligand design introduced a reactive aminopropyl group at the polar lipid head of the ring-phosphorylated phosphoinositides, allowing a reporter moiety to be positioned at the surface of the bilayer and in the vicinity of the phosphorylated inositol. Such reporter groups may interact with membrane-proximal regions of PIP2- and PIP3-binding proteins recruited to membrane sites by electrostatic interactions between the phosphates of the phospholipid and basic regions of the proteins. Following a convergent strategy, phosphitylation of an optically-pure 1,2-O-diacyl-sn-glycerol with 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite was followed by coupling with protected inositol precursors to give adducts 8 in 80% to 95% yield. The 2-cyanoethyl phosphotriester was stable during the subsequent reaction steps and could be conveniently converted to the 3-aminopropyl group during the final hydrogenolysis of the benzyl protecting groups. Benzophenone-containing photoaffinity probes of the phosphotriester 11a and 11b were also synthesized. Alternatively, the versatile cyanoethyl group could be removed using diisopropylethylamine prior to hydrogenolysis, thereby furnishing the corresponding phosphodiesters, PIP3 and PIP2 (13a and 13b).
