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Title: Synthesis of optically-labelled vanadyl complexes and their evaluation as protein tyrosine phosphatase inhibitors and intracellular probes
Author: Collins, Juliet Claire
ISNI:       0000 0004 5989 7764
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Cysteine based phosphatases (CBPs) are a diverse family of enzymes that act to remove the phosphate group from proteins, phosphatidylinositols and other biomolecules, thereby counteracting the effects of kinases. Due to the wide range of roles they play in the cell, the CBPs are implicated in many diseases such as cancer, diabetes and neurodegenerative disorders, and therefore it is of interest to develop compounds to study these enzymes. Within our group, vanadium compounds have been shown to inhibit the CBPs with a potency and selectivity that can be tuned by varying the ligand and the oxidation state of the vanadium centre. One subset of interest is the vanadium complexes of 3-hydroxypicolinic acid which have an inhibition range against phosphatases of low nanomolar to high micromolar depending on the oxidation state of vanadium and the enzyme studied. A small selection of novel fluorescent vanadyl complexes based on the hydroxypicolinic acid motif have been synthesised as novel phosphatase inhibitors. Incorporation of an amine-functionalised spacer between the picolinate ligands provided a handle for incorporation of a fluorescent group away from the picolinate-vanadyl core. These compounds were then tested against a range of phosphatases to determine their potency and selectivity as inhibitors of CBPs. The complexes showed good inhibition properties against the CBPs investigated in a range similar to that of free vanadyl. The fluorophore was used to study the interaction of the vanadyl complexes with the enzymes, and to investigate cell uptake. Fluorescence quenching and anisotropy assays were carried out to look at the stability of complexes in assay conditions. From the data obtained it appears that the vanadyl complexes are stable in the presence of the enzymes and under assay conditions. Preliminary data also indicate that the complexes are taken up into cells and therefore can be investigated as intracellular probes.
Supervisor: Vilar, Ramon ; Woscholski, Rudiger ; Leatherbarrow, Robin Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral