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Targeted Multi-Modal Imaging: Using The Ugi Reaction With Metals
[Thesis]. Manchester, UK: The University of Manchester; 2012.
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Abstract
The current “gold standard method” of detecting cancer relies on microscopic examination by specialised pathologists.33 However, there are risks associated with surgery and biopsies and so the ability to diagnose cancer and other diseases in a non-invasive manner is highly attractive. There are many imaging techniques suitable for this, each with their own advantages and disadvantages, which can be improved by the use of contrast agents.12, 34-37 The incorporation of targeting vectors allows for the specific imaging of desired tissues.12, 38-41 Further to this, the incorporation of more than one contrast agent into one imaging agent allows for multi-modal imaging of cancerous tissue and other diseases. This allows for the advantages of different techniques to be used simultaneously and is an emerging field.37 The methods for the synthesis of these drugs can be synthetically demanding and low yielding due to linear synthetic strategies. The use of multi-component reactions would be a major benefit and the Ugi reaction is particularly attractive due to the incorporation of four components and the biocompatible bis-amide motif of Ugi products.42, 43This work serves as an extension to previous work based on Ugi reactions of metal complexes, which showed that amine and carboxylic acid appended lanthanide and carboxylic acid appended d-metal complexes can be used as stable building blocks in the formation of mono-metallic complexes.1, 2 This work presents the synthesis of aldehyde appended lanthanide complexes and their use in Wittig and Ugi chemistry in the synthesis of mono-metallic complexes. The previously synthesised amine appended lanthanide complexes1, 3, 4 were also synthesised to be used as a feedstock in subsequent Ugi reactions. A number of carboxylic acid appended d-metal complexes and cyanine dyes were synthesised according literature procedures.1, 13, 14, 44-49 Both the bis-acid appended d-metal complexes and cyanine dyes were used unsuccessfully in the Ugi reaction. However, the mono-acid d-metal complexes were used successfully in the Ugi reaction in keeping with previous reports.1 These were used as the third feedstock for the synthesis of trimetallic complexes along with the aldehyde and amine appended lanthanide complexes via the Ugi reaction.In addition, a number of Ugi reactions were performed on organic compounds. The use of p-toluic acid gave five Ugi compounds, which were characterised and gave the expected results. However, the use of biotin as the carboxylic acid component gave four compounds that were complex to characterise and suggested that the incorporated biotin may not serve as a viable targeting vector. One of the p-toluic acid Ugi products was reacted further and a biotin moiety was incorporated with a (CH2)6 spacer. Spectroscopic evidence suggested that the biotin would still act as a viable targeting vector.Overall, this work serves to set the scene for the synthesis of targeted tri-metallic multi-modal imaging agents using stable metal complexes as building blocks in the Ugi reaction.