Asif Noor

Active-template synthesis of "click" (2)rotaxane ligands: self-assembly of mechanically interlocked metallo-supramolecular dimers, macrocycles and oligomers†

Due to potential applications in the biological and material sciences there is considerable interest in the development of mechanically interlocked ligands (MILs). The mild functional-group tolerant copper(I)-catalysed azide–alkyne cycloaddition active-metal-template (CuAAC-AMT) method has been exploited to generate mono- and bi-functionalised [2]rotaxanes by interlocking an exo-alcohol functionalised macrocycle and functionalised triphenylmethyl stoppers. These [2]rotaxanes were post-synthetically conjugated to either one or two 2,2′,6′,2′′-terpyridine (terpy) coordinating units to generate mechanically interlocked “super” ligands. Addition of Fe(II) ions to the mono-terpy ligand leads to the formation of a metallo-bis-([2]rotaxane). At high dilution the bi-terpy [2]rotaxane ligand forms a [2]rotaxane metallo-macrocycle, in the presence of Fe(II) ions. Conversely, at high concentration self-assembly of the bi-terpy [2]rotaxane ligand with Fe(II) ions results in the generation of a metallo-supramolecular poly-[2]rotaxane oligomer. The [2]rotaxane ligands and corresponding Fe(II) complexes have been characterised with 1H and 13C NMR and UV-vis spectroscopies, high resolution electrospray ionisation mass spectrometry (HR-ESMS), and elemental analyses. Additionally, 1H DOSY NMR spectroscopy and GPC analysis were used to provide evidence for the constitution of the self-assembled metallo-supramolecular mechanically-interlocked architectures.

A multi-component CuAAC ‘click’ approach to an exo functionalised pyridyl-1,2,3-triazole macrocycle: synthesis, characterisation, Cu(I) and Ag(I) complexes

A one-pot, multi-component CuAAC reaction was exploited for the safe generation of an exo alcohol-functionalised pyridyl-1,2,3-triazole ‘click’ macrocycle in good yield. The macrocycle was characterised by elemental analysis, HR-ES-MS, 1H and 13C NMR spectrometry, and the molecular structure was confirmed by X-ray crystallography. Efforts to use the ‘click’ macrocycle in both passive and active metal template syntheses of [2]rotaxanes were unsuccessful, and this appears to be connected to the coordinating ability of the 1,2,3-triazole units in the macrocycle. The coordination chemistry of the macrocycle with Cu(I) and Ag(I) was examined. It has been demonstrated using HR-ES-MS, 1H NMR spectrometry and X-ray crystallography that the macrocycle can form both discrete and polymeric coordination compounds with Cu(I) and Ag(I) and in all cases the 1,2,3-triazolyl units of the macrocycle are coordinated to the metal ions.

Effect of Structural Modifications to Glyoxal-bis(thiosemicarbazonato)copper(II) Complexes on Cellular Copper Uptake, Copper-Mediated ATP7A Trafficking, and P-Glycoprotein Mediated Efflux

Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293, and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway. Treatment of SKOV-3 cells with low concentrations (μM) of two of the copper complexes led to trafficking of the endogenous copper transporter ATP7A from the Golgi network to the cell membrane. Experiments in HEK293 and HEK293-P-gp cells suggest that Cu(gtsm) and Cu(gtse) are substrates for the P-gp efflux protein but the complex with a pyrrolidine functional group, Cu(gtspyr), is not. A PET experiment in mice showed that [64Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake.