The application of the click reaction in the synthesis of targeted drugs and MRI contrast agents.

The click reaction is a versatile tool in synthetic chemistry and in this thesis, the applicability of this reaction in the synthesis of targeted drugs and MRI contrast agents has been assessed. In the first part of the research, the reaction was used to construct conjugates of targeting agents and cytotoxic drugs, with applications in cancer treatment. The conclusions in this first part are dual, on one hand, the reaction, on one hand the reaction prevented the synthesis of a number of tirapazamine analogues (most likely due to the formation of insoluble copper complexes), on the other hand, the modular nature of the reaction and its orthogonality with most other reactions proved to enable and facilitate the synthesis of conjugates of RGD mimetics with tubuline polymerization inhibitors and conjugates of an NLS-peptide with a BODIPY PDT probe.In the second part of the thesis, the click reaction as a tool in the synthesis of specific MRI contrast agents has been evaluated. Firstly, the click reaction was used to demonstrate the ease and feasibility of the synthesis of small molecular weight target specific MRI contrast agents. Here, azide substituted target specific probes were fused to an alkyne bearing GdDOTA analogue and the physical and biological properties of the contrast agent proved its effectiveness in vitro.A second type of contrast agents, consisting of a Ru2+ based metallostar contrast agent decorated with RGD-peptides, was constructed. Here, the click reaction s orthogonality enabled the decoration to be postponed to the final step, thus allowing the introduction of the peptides under relatively mild conditions. Due to the modular nature of the click reaction, the scaffold used here could be used as a building block of analogous metallostars decorated with different specific probes.status: publishe