Synthesis and Evaluation of 5-Fluorotriazole Cyclam Complexes as Target Activated Metal Complexes

Abstract

Metal containing drugs remain an important class of compounds due to their exquisite potency, however their clinical use is often limited by poor selectivity. The overall aim of this thesis is to develop and investigate cyclam fluorotriazolyl derivates for sensing applications by exploiting the versatile metal-binding capability of cyclam and the synthetic simplicity of the CuAAC reaction to obtain target triazolyl derivatives. A variety of metal-cyclam-based systems have been investigated for potential in monitoring triazole connectivity and biological binding events. In Chapter two, an efficient synthesis of 5-fluorotriazole-cyclam metal complexes has been developed in which the pendant group is connected to cyclam via N1. A halogen-exchange protocol has been used to access fluorinated-triazole systems. 19F NMR and 1H NMR confirm the presence of conformational isomers. In Chapter three, ligand-induced displacement of the pendant triazole from the metal centre of the complexes described in Chapter two was used to simulate changes to the metal coordination environment as were observed upon binding of biotinylated cyclam complexes to avidin. Mass spectrometry and 19F NMR spectroscopy confirm successful triazole displacement. Collectively these results establish 5-fluorotriazole-cyclam complexes as promising molecules for 19F-based coordination sensing. This work provides a foundation for applying 19F NMR as a sensitive and versatile method for probing more complex coordination events in biological systems.