Synthesis of deuterated phosphatidylinositol phosphates

Thesis

Phosphatidylinositol phosphates (PtdInsP_n) are intracellular signalling molecules that are important in many key biological processes, in particular Ca²⁺ signalling pathways. Dysfunction of these processes has been implicated in numerous diseases including diabetes and many cancers. Some aspects of PtdInsP_n signalling have been heavily investigated; PTEN, PKC/Akt, PtdIns3K and PtdIns4K are all important therapeutic targets that have seen much attention in industrial endeavours. Inositol-based probes and tool compounds for these targets typically incorporate a fluorescent tag or photo-crosslinking group, usually at the lipid tails. It is increasingly apparent that the nature of the lipid chains plays a key role in determining the sub-cellular localisation of the PtdInsP_n and hence modification of the lipids is potentially detrimental to the biological function of the tool compounds. An additional challenge in the development of inositol-based tools compounds is the difficult and lengthy syntheses that are employed to obtain the target compounds. To address this, we have developed a novel asymmetric route that allows rapid synthesis of PtdIns and PtdIns(4,5)P₂. This route has been designed to allow incorporation of multiple deuterium atoms onto the myo-inositol ring (C-perdeuterated). To achieve this, we began with the aromatic compound quinol and built up the myo-inositol ring piecewise, allowing for deuterium incorporation. This methodology utilised a Pd-catalysed dynamic kinetic resolution on a conduritol B derivative to form optically-pure myo-inositol derivatives in high e.e. (>99%) toward the synthesis of D₆-PtdIns(4,5)P2. The incorporation of deuterium into these compounds should be minimally disruptive to their biological activity, while the difference in molecular mass between the endogenous and tool compounds enables their use in a range of biological assays. In addition, the incorporation of the deuterium onto the myo-inositol ring will allow for the detection of downstream effects relating to the myo-inositol ring post-hydrolysis of PtdIns(4,5)P₂ to be observed, which is currently not possible with other probes.

Authors: Saunders, A

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Deuterium Labelling; Phospholipids
• Subjects: Organic compounds--Synthesis