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Synthesis of Diphosphoinositol Polyphosphates


Capolicchio, Samanta. Synthesis of Diphosphoinositol Polyphosphates. 2015, University of Zurich, Faculty of Science.

Abstract

Diphosphoinositol polyphosphates (PP-InsPy) represent a novel group of secondary messengers that regulate diverse important cellular processes, including signal transduction, vesicle trafficking and apoptosis. Recently, it has been reported that PP-InsPy phosphorylate proteins in a process known as protein pyrophosphorylation. This new type of posttranslational modification occurs in vitro, but it is still unclear if it occurs also in vivo. The concentration of PP-InsPy in cells is very low which makes their isolation from biological sources difficult. PP-InsPy have been prepared enzymatically. However, this method does not permit to obtain large amount of material necessary for biological studies. Additionally, it is not suitable for the preparation of non-natural isomers and the stereochemistry of the synthesized molecules cannot be assigned. Therefore, an efficient method to prepare a scalable amount of PP-InsPy is essential to study the structure and functions of PP-InsPy. The preparation of PP-InsPy by chemical synthesis offers the best opportunities to prepare a scalable amount of material with known stereochemistry. Additionally, this method can provide the access to several non-natural derivatives that can be used as chemical tools to study the metabolism of PP-InsPy. Different syntheses of enantiomerically pure inositol polyphosphates have been reported, but PP-InsPy are not commercially available and the quality of earlier preparations has been called into question. Asymmetric phosphorylation is an outstanding way to introduce a phosphate group in a specific position in the structure of myo-inositol. We will report a novel total synthesis of unsymmetric diphosphoinositol polyphosphates using a C2-symmetric phosphoramidite to desymmetrize different inositol derivatives. This novel phosphorylating reagent enabled us to target all four possible unsymmetric X-PP-InsP5 (1-PP-InsP5, 3-PP-InsP5, 4-PP-InsP5 and 6-PP-InsP5). Additionally, 1,5-(PP)2-InsP4 and 3,5-(PP)2-InsP4 were prepared for the first time with the same methodology. A novel synthesis of the symmetric 5-PP-InsP5 and the first total synthesis of meso 5-PPP-InsP5 will be also reported. These results represent a new approach in the envisaged total syntheses of PP-InsPy as well as the starting point for the development of efficient reagents for asymmetric phosphorylation and pyrophosphorylation. Additionally, it provided us with tools that can be used to decipher inositol related cellular signalling pathways.

Abstract

Diphosphoinositol polyphosphates (PP-InsPy) represent a novel group of secondary messengers that regulate diverse important cellular processes, including signal transduction, vesicle trafficking and apoptosis. Recently, it has been reported that PP-InsPy phosphorylate proteins in a process known as protein pyrophosphorylation. This new type of posttranslational modification occurs in vitro, but it is still unclear if it occurs also in vivo. The concentration of PP-InsPy in cells is very low which makes their isolation from biological sources difficult. PP-InsPy have been prepared enzymatically. However, this method does not permit to obtain large amount of material necessary for biological studies. Additionally, it is not suitable for the preparation of non-natural isomers and the stereochemistry of the synthesized molecules cannot be assigned. Therefore, an efficient method to prepare a scalable amount of PP-InsPy is essential to study the structure and functions of PP-InsPy. The preparation of PP-InsPy by chemical synthesis offers the best opportunities to prepare a scalable amount of material with known stereochemistry. Additionally, this method can provide the access to several non-natural derivatives that can be used as chemical tools to study the metabolism of PP-InsPy. Different syntheses of enantiomerically pure inositol polyphosphates have been reported, but PP-InsPy are not commercially available and the quality of earlier preparations has been called into question. Asymmetric phosphorylation is an outstanding way to introduce a phosphate group in a specific position in the structure of myo-inositol. We will report a novel total synthesis of unsymmetric diphosphoinositol polyphosphates using a C2-symmetric phosphoramidite to desymmetrize different inositol derivatives. This novel phosphorylating reagent enabled us to target all four possible unsymmetric X-PP-InsP5 (1-PP-InsP5, 3-PP-InsP5, 4-PP-InsP5 and 6-PP-InsP5). Additionally, 1,5-(PP)2-InsP4 and 3,5-(PP)2-InsP4 were prepared for the first time with the same methodology. A novel synthesis of the symmetric 5-PP-InsP5 and the first total synthesis of meso 5-PPP-InsP5 will be also reported. These results represent a new approach in the envisaged total syntheses of PP-InsPy as well as the starting point for the development of efficient reagents for asymmetric phosphorylation and pyrophosphorylation. Additionally, it provided us with tools that can be used to decipher inositol related cellular signalling pathways.

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Additional indexing

Item Type:Dissertation
Referees:Robinson John Anthony, Jessen Henning Jacob, Sigel Roland K O
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2015
Deposited On:27 Feb 2015 12:19
Last Modified:05 Apr 2016 18:55

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