Functionalising Metal Complexes

One of the major advantages of the use of metal complexes in medicinal chemistry is their ability to affect a wide range of chemical and biological properties by modification of the coordinated ligands.29,138Traditionally, these properties are tuned

viathe binding of different ligands to the metal complexes. For example, the use of a pyridine monodentate ligand in N,N-chelated Ru(II) arene complexes blocks the reactivity of the monodentate site towards hydrolysis and nucleobase binding, but the complex can be photoactivated to release the pyridine ligand.139,140 This allows

for controlled DNA binding and hence a greater control over the cytotoxic properties of the complex.

The ability to add organic fragments that exert a particular function in the resulting complex, such as aiding selectivity towards uptake in cancerous cells over healthy cells, or delivery to a particular organelle, is an expanding area of research.141Pt(II) anticancer complexes cisplatin, carboplatin and oxaliplatin have been functionalised for active drug transport and deliveryviaconjugation to organic/bioorganic moieties such as estrogens, carbohydrates and peptides.142 Metal complexes can also be modified to attach them to nanoparticles, carbon-nanotubes and polymers.143-145This can be advantageous for exploiting the enhanced permeability and retention (EPR) effect, where molecules of high molecular weight (such as polymers) accumulate in tumour tissue to a greater extent than in healthy cells. Polymer systems can also be decorated with molecules to enhance receptor-mediated targeting, further increasing their drug delivery and selectivity.146

Post-modifications to metal complexes allow for a diverse range of new complexes to be prepared from one “parent” complex, without the need to make individual ligands for coordination to the metal. In order to post-functionalise metal complexes, a functional group is generally required on one of the ligands (unless the complex is functionalised via addition of a ligand) that confers a particular reactivity towards another functional group. Metzler Nolte et al. have pioneered the bioconjugation of peptides and PNA oligomers to ferrocenyl and octahedral metal complexes using click chemistry147 and Sonogashira coupling148 which require the presence of an azide/alkyne or alkyne/iodide group, respectively (Figure 1.19).

Figure 1.19 Bio-conjugation of ferrocenyl and octahedral metal complexes to the peptide enkephalin using (A) Sonogashira coupling and (B) “click-chemistry”. The use of aldehyde groups on ligands to functionalise metal complexes has recently gained some attention. The advantage of using this system is the high reactivity that aldehydes have towards nucleophilic attack by amines, which allows both organic and bioorganic amines such as peptides and proteins (which contain a free amino group) to be conjugated without using highly forcing conditions. The condensation reaction produces the imine functional group (Figure 1.20), also known as a Schiff base, which is susceptible to hydrolysis and is enhanced at acidic pH. In polymer research, this has led to the development of polymers that contain pH-sensitive imine

bonds as drug delivery vehicles for cancer drugs, where upon hydrolysis in the more acidic microtumour environment the drugs are preferentially released in cancer cells.149,150

Figure 1.20 Reaction of benzaldehyde with 2-methoxylethylamine to form the corresponding imine conjugate.

The exploitation of the reactivity of aldehyde groups on a Pt(II)-NHC complex was recently demonstrated by Bellemin-Laponnaz et al., who showed that either primary amines or hydroxylamines can form imines or oximes, respectively.151 C-protected amino acids can be easily conjugated to the complex to form Schiff bases, and it was even demonstrated that the reduction of the imine to the secondary amine can be performed using the weak reducing agent NaHB(OAc)3. Lo et al. have also demonstrated how an octahedral Ir(III) complex bearing aldehyde substituents can react with bovine serum albumin (BSA) via surface lysine residues, followed by reduction using NaCNBH3 to form stable Ir(III)-bioconjugates with luminescent properties.152

1.7

Aims

Due to promising results reported for the use of C,N-chelated iridium(III) half- sandwich complexes as anticancer agents, a major part of this thesis is concerned with the further study of this series, with particular focus on tuning the properties

and activities of Cp* compounds viafunctionalisation of chelating and monodentate ligands. Iminopyridine N,N-chelated iridium(III) complexes were also investigated, examining the effects that functionality on the Cpxring and chelating ligand have on the chemical, antibacterial and anticancer activity. More specific aims were as follows.

1. Synthesis, characterisation and evaluation of the chemical, physicochemical and anticancer properties that arise from functionalising 2-phenylpyridine ligands in complexes of the type [(η5-Cp*)Ir(2-phenylpyridine)Cl] with electron-donating and electron-withdrawing groups.

2. Studying the effects on the chemical and anticancer properties of chlorido and pyridyl monodentate ligands on the complex [(η5-Cp*)Ir(2-(2ˈ- methylphenyl)pyridine)X]0/+.

3. Exploring the functionalisation of the anticancer complex [(η5-Cp*)Ir(2-phenyl-5-pyridinecarboxaldehyde)Cl] by reactions with amines and peptides to form new Schiff base conjugates, including the addition of a fluorescent dansyl moiety. Reduction of the dansyl conjugate to the secondary amine was investigated to enable investigations into tracking the complexviaconfocal microscopy.

4. The synthesis, characterisation and evaluation of the solution chemistry of complexes of the type [(η5-Cpx)Ir(phenyliminopyridyl)Cl]PF6 with investigations into their antibacterial and anticancer activity.