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Title: Synthesis of novel phospholipid-based chemical probes for biological systems
Author: Johns, M. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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The cyclitol myo-inositol 1.1 is a component of a large number of biomolecules, many of which are of great biological importance due to their involvement in intracellular signalling cascades. Although understanding of the phosphoinositol cycle has advanced significantly over recent years, many of aspects of the associated signalling pathways remain unclear. This dissertation focuses on the synthesis of modified phospholipids for use as biological process with the aim of improving the understanding of the molecular basis of their functions. As well as working on phosphoinositol problems, functionalised analogues of the phospholipids phosphatidic acid (PA) and cardiolipin have also been synthesised. (Fig. 6222A) Chapter 2 provides a summary of the phosphoinositide pathway and outlines the current understanding of the functions of the phosphatidylinositol polyphosphates (PIPnS). The role of defective phosphoinositide signalling pathways in disease is also discussed. General considerations for designing the synthesis of phosphorylated inositol derivatives are described in Chapter 2. recent syntheses of phosphoinositides are reviewed, with particular emphasis on the preparation of optically pure, protected intermediates. The development of modified phosphoinositides for the investigation of cell signalling pathways is also covered. (Fig. 6222B) Chapter 3 begins with a brief review of the functions and previous syntheses of the membrane phospholipids, cardiolipin. The synthesis of covalently immobilised cardiolipin 3.53 is described and was achieved from the chiral glycerol derivative (+)-3.63 using phosphoramidite chemistry to introduce the phosphodiester linkages. This affinity matrix will be used to isolate cardiolipin-binding proteins which may contribute to an improved understanding of the roles of this phospholipids and its involvement in disease. (Fig. 6222C) Chapter 4 describes the synthesis of cell membrane permeant analogues of PA from the chiral acetal (+)-3.63. PA analogues were synthesised bearing both one and two phenacyl caging groups at the phosphate headgroup, (+)-4.41 and (+)-4.80 respectively, together with a fluorescently-tagged analogue (+)-4.67 to investigate the ability of these lipids to cross the plasma membrane by passive diffusion. (Fig. 6222D) Also discussed in Chapter 4 is the preparation of an advanced intermediate for the synthesis of cell membrane permeant phosphatidylinositol 3,4-bisphosphate 4.114. this was achieved from myo­-inositol orthoformate 2.78 using a regioselective DIBAL-H-mediated reduction and resolution via the camphor acetal (-)-4.95. (Fig. 6222E) Chapter 5 reports progress towards the synthesis of C-5 phosphinate-modified inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] analogues 5.5 as potential antagonists of Ins(1,4,5)P3-mediated calcium release. The synthesis again began with the orthoformate 2.78 and used camphor acetal formation to resolve the protected intermediates. A regioselective alkylation strategy involving formation of a stannylene was used to differentiate the C-3 and -4-hydroxyl groups. (Fig. 6222F) The synthesis of immobilised phosphatidylinositol 6.1 and phosphatidylinositol 4-phosphate 6.2 are described in Chapter 6 using an extension of the methodology described in the preceding chapters.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available