Bridging Metals and Peptides: Introducing selectivity to transition metal complexes towards targeted cancer therapy

Abstract

Metal-based anticancer agents are a prominent feature in chemotherapeutics. Ruthenium complexes show increasing popularity over traditional platinum-based drugs to explore more selective and less toxic treatment options. Depending on the ligand of choice, organometallic compounds have are promising against primary tumours or metastases and “piano-stool” complexes of the general formula [MII/III(arene/Cp*(X)(Y)(Z)] have demonstrated to be particularly efficacious against primary tumours or metastases. The hydrophobic ring system gives the complex the ability to transverse through cell membranes into the cell, while the X, Y, and Z legs of the piano stool may be mono- or multidentate ligand systems such as bioactive moieties or anionic leaving groups, tunable for specific activity. In this doctoral thesis, a library of metal-based N-heterocyclic carbene (NHC) complexes was synthesised based upon the piano-stool scaffold and characterised in terms of their chemical structure and their biological activity against different human cancer cell lines, showing moderate anticancer activity. Thioredoxin reductase (TrxR) inhibition studies showed unexpected potent inhibition was exhibited by the two Rh derivatives in the library, which will hopefully lead to the development of a generation of new compounds. To introduce selectivity to piano-stool complexes and thereby reduce toxicity, a novel solid phase strategy was adopted to effect carbene activation on solid resin support, involving the conjugation of Ru(NHC) complexes to peptides utilising the carbene ligand system in the Ru(NHC) complex as the anchor. Selective conjugation was performed at different locations on the peptide backbone to compare synthetic accessibility as well as structure-activity relationship. All compounds were readily synthesised and purified, affording the products in high yields. The peptide conjugates synthesised in this manner were found to be stable to peptide isolation and purification, opening the door for many opportunities in the field of bioorganometallic chemistry. The novel strategy was then applied to Os-, Rh-, and Ir(NHC) complexes. Choosing a peptide capable of targeting cell compartments and conjugating it to the different transition metal centres to compare accessibility and reproducibility of the conjugation strategy and comparing structure-activity relationships. The compounds were tested for antiproliferative activity in human cancer cell lines but were shown to be not cytotoxic. Despite a lack of cytotoxic activity, the work highlights a new and very useful tool in hand to further develop metallodrugs with targeting capabilities.