Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate.

Diphospho-myo-inositol phosphates (PP-InsP(y)) are an important class of cellular messengers. Thus far, no method for the transport of PP-InsP(y) into living cells is available. Owing to their high negative charge density, PP-InsP(y) will not cross the cell membrane. A strategy to circumvent this issue involves the generation of precursors in which the negative charges are masked with biolabile groups. A PP-InsP(y) prometabolite would require twelve to thirteen biolabile groups, which need to be cleaved by cellular enzymes to release the parent molecules. Such densely modified prometabolites of phosphate esters and anhydrides have never been reported to date. This study discloses the synthesis of such agents and an analysis of their metabolism in tissue homogenates by gel electrophoresis. The acetoxybenzyl-protected system is capable of releasing 5-PP-InsP5 in mammalian cell/tissue homogenates within a few minutes and can be used to release 5-PP-InsP5 inside cells. These molecules will serve as a platform for the development of fundamental tools required to study PP-InsP(y) physiology.

[1]  A. Saiardi,et al.  VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP8 and Jasmonate-Dependent Defenses in Arabidopsis[OPEN] , 2015, Plant Cell.

[2]  Z. Xi,et al.  Synthesis and in vitro anticancer activity evaluation of novel bioreversible phosphate inositol derivatives. , 2015, European journal of medicinal chemistry.

[3]  A. Saiardi,et al.  A novel method for the purification of inositol phosphates from biological samples reveals that no phytate is present in human plasma or urine , 2015, Open Biology.

[4]  J. Balzarini,et al.  Nucleoside Mono‐ and Diphosphate Prodrugs of 2′,3′‐Dideoxyuridine and 2′,3′‐Dideoxy‐2′,3′‐didehydrouridine , 2015, ChemMedChem.

[5]  A. Wiemer,et al.  Prodrugs of phosphonates and phosphates: crossing the membrane barrier. , 2015, Topics in current chemistry.

[6]  Huanchen Wang,et al.  Synthesis of densely phosphorylated bis-1,5-diphospho-myo-inositol tetrakisphosphate and its enantiomer by bidirectional P-anhydride formation. , 2014, Angewandte Chemie.

[7]  R. Schinazi,et al.  Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs , 2014, Chemical reviews.

[8]  André Nadler,et al.  Caged lipids as tools for investigating cellular signaling. , 2014, Biochimica et biophysica acta.

[9]  D. Fiedler,et al.  Elucidating diphosphoinositol polyphosphate function with nonhydrolyzable analogues. , 2014, Angewandte Chemie.

[10]  A. M. Riley,et al.  Synthetic Inositol Phosphate Analogs Reveal that PPIP5K2 Has a Surface-Mounted Substrate Capture Site that Is a Target for Drug Discovery , 2014, Chemistry & biology.

[11]  Nisar Ahmed,et al.  Phosphate esters and anhydrides--recent strategies targeting nature's favoured modifications. , 2014, Organic & biomolecular chemistry.

[12]  J. Balzarini,et al.  The DiPPro Approach: Synthesis, Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs , 2014, ChemMedChem.

[13]  R. Pepperkok,et al.  PIP3 Induces the Recycling of Receptor Tyrosine Kinases , 2014, Science Signaling.

[14]  A. Saiardi,et al.  Analysis of Dictyostelium discoideum Inositol Pyrophosphate Metabolism by Gel Electrophoresis , 2014, PloS one.

[15]  H. Jessen,et al.  Iterative Synthese von Nukleosidoligophosphaten mit Phosphoramiditen , 2014 .

[16]  H. Jessen,et al.  Iterative synthesis of nucleoside oligophosphates with phosphoramidites. , 2014, Angewandte Chemie.

[17]  B. Potter,et al.  The enzymes of human diphosphoinositol polyphosphate metabolism , 2013, The FEBS journal.

[18]  R. S. Kilari,et al.  Understanding inositol pyrophosphate metabolism and function: Kinetic characterization of the DIPPs , 2013, FEBS letters.

[19]  A. Linden,et al.  Synthesis of unsymmetric diphospho-inositol polyphosphates. , 2013, Angewandte Chemie.

[20]  A. Saiardi,et al.  Inositol pyrophosphates: between signalling and metabolism. , 2013, The Biochemical journal.

[21]  Frank Noé,et al.  Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate , 2013, Nature.

[22]  M. Wymann,et al.  The Chemical Biology of Phosphoinositide 3‐Kinases , 2012, Chembiochem : a European journal of chemical biology.

[23]  Carsten Schultz,et al.  Photoaktivierbares und zellmembranpermeables Phosphatidylinositol‐3,4,5‐trisphosphat , 2011 .

[24]  V. Laketa,et al.  Photoactivatable and cell-membrane-permeable phosphatidylinositol 3,4,5-trisphosphate. , 2011, Angewandte Chemie.

[25]  G. Prestwich,et al.  Inositol polyphosphates, diphosphoinositol polyphosphates and phosphatidylinositol polyphosphate lipids: structure, synthesis, and development of probes for studying biological activity. , 2010, Natural product reports.

[26]  R. Pepperkok,et al.  Activation of membrane-permeant caged PtdIns(3)P induces endosomal fusion in cells. , 2010, Nature chemical biology.

[27]  R. Pepperkok,et al.  Membrane-permeant phosphoinositide derivatives as modulators of growth factor signaling and neurite outgrowth. , 2009, Chemistry & biology.

[28]  S. Shears.  Diphosphoinositol Polyphosphates: Metabolic Messengers? , 2009, Molecular Pharmacology.

[29]  M. Berridge,et al.  Inositol trisphosphate and calcium signalling mechanisms. , 2009, Biochimica et biophysica acta.

[30]  A. Saiardi,et al.  Inositol Pyrophosphates and Their Unique Metabolic Complexity: Analysis by Gel Electrophoresis , 2009, PloS one.

[31]  C. Meier,et al.  Bioreversible Maskierung von Nucleosiddiphosphaten , 2008 .

[32]  J. Balzarini,et al.  Bioreversible protection of nucleoside diphosphates. , 2008, Angewandte Chemie.

[33]  J. Honek,et al.  Phosphate transfer from inositol pyrophosphates InsP5PP and InsP4(PP)2: a semi-empirical investigation. , 2007, Bioorganic & medicinal chemistry letters.

[34]  A. Saiardi,et al.  Inositol pyrophosphates: metabolism and signaling , 2006, Cellular and Molecular Life Sciences.

[35]  Carsten Schultz,et al.  Membranpermeable 3-OH-phosphorylierte Phosphoinositidderivate† , 2001 .

[36]  C. Schultz,et al.  Membrane-Permeant 3-OH-Phosphorylated Phosphoinositide Derivatives. , 2001, Angewandte Chemie.

[37]  M. Schell,et al.  Back in the water: the return of the inositol phosphates , 2001, Nature Reviews Molecular Cell Biology.

[38]  A. M. Riley,et al.  Inositol 1,3,4-Trisphosphate Acts in Vivo as a Specific Regulator of Cellular Signaling by Inositol 3,4,5,6-Tetrakisphosphate* , 1999, The Journal of Biological Chemistry.

[39]  Roger Y. Tsien,et al.  Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression , 1998, Nature.

[40]  R. Tsien,et al.  Membrane-permeant esters of inositol polyphosphates, chemical syntheses and biological applications☆ , 1997 .

[41]  B. Potter,et al.  Chemistry of Inositol Lipid Mediated Cellular Signaling , 1995 .

[42]  J. Imbach,et al.  Mononucleoside phosphotriester derivatives with S-acyl-2-thioethyl bioreversible phosphate-protecting groups: intracellular delivery of 3'-azido-2',3'-dideoxythymidine 5'-monophosphate. , 1995, Journal of medicinal chemistry.

[43]  Barry V. L. Potter,et al.  Die Chemie der Inositlipid‐vermittelten zellulären Signalübertragung , 1995 .

[44]  R. Tsien,et al.  Long-term uncoupling of chloride secretion from intracellular calcium levels by lns(3,4,5,6)P4 , 1994, Nature.

[45]  W. J. Irwin,et al.  Synthesis, bioactivation and anti-HIV activity of the bis(4-acyloxybenzyl) and mono(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT , 1993 .

[46]  M. Caruthers,et al.  Deoxynucleoside phosphoramidites—A new class of key intermediates for deoxypolynucleotide synthesis , 1981 .