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Title: Design and synthesis of transition metal-polyamine conjugates for diagnostic and therapeutic applications
Author: Phillips, Stuart Gordon
ISNI:       0000 0004 7227 9581
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2015
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The polyamine transport system is upregulated in many cancer cell lines and is seen as a potential method of delivery for diagnostic and therapeutic agents. A series of transition metal-polyamine complexes have been synthesised using the CuAAC reaction to synthesise a carboxylic acid-containing pyridyltriazole (pyta) diimine ligand, 34, for functionalisation and coordination to rhenium(I), iridium(III) and platinum(II), and a tandem, one-pot diazotransfer/CuAAC reaction has been developed allowing clean and rapid access to the conjugated pyta ligands L3d.Boc, L3e.Boc and L3f.Boc in moderate to good yields. The conjugates exhibit the expected photophysical properties of such metal-ligand complexes (MLCs) and appear insensitive to changes in pH and dissolved oxygen content. Excitation at 330 nm gives rise to emission at 511 nm. Conjugates, and Ir.L3e have quantum yields (H2O at pH 7.4) of 0.0029, 0.0020 and 0.0491, respectively, and lifetimes in the region of ~60 ns (Re) and ~385 ns (Ir). Some of the conjugates have been tested in vitro and have been shown to be internalised in A549 lung cancer cells and localised in vesicular-like structures in the perinuclear region, but it is yet to be proved that they exploit the polyamine transport system (PTS). Iridium(III) conjugate Ir.L3f was used in preliminary experiments as a potential probe for synaptic function, visualising putative pre-synaptic terminals in early images. Platinum(II) conjugate Pt.L3d has been synthesised and is awaiting further testing to assess its ability to bind DNA. The conjugates were designed to be able to incorporate a chemically labile linker for the selective release of a chemotherapeutic drug. UV and fluorescence spectroscopy experiments which support the theory of the endosomal release through the rapid hydrolysis of a hydrazone bond at mildly acidic pH have been successfully conducted, showing a half-life of ~13 hr at pH 7.4 and ~18 min at pH 5.0.
Supervisor: Cullis, Paul ; Lowe, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available