CHAPTER 9: Biomolecular Interactions of Platinum Complexes

Deoxyribonucleic acid is generally accepted as the primary biomolecular target of the first platinum-based chemotherapeutic agent, cisplatin, which was documented in 1845, characterised in 1893 and its potential discovered in 1965. Initial attempts to understand the structural significance of the compound by combinatorial means saw early conceptions of structure–activity relationships that were soon challenged. Almost 50 years and thousands of complexes later, DNA still remains the primary target in a variety of interactions ranging from differences in base-pair preference, irreversible covalent binding, and reversible minor/major groove binding and intercalation. Developmental efforts have seen active cytotoxic platinum complexes with structures derived beyond initial assumptions through a diversity of ligand substitution and multinuclear linkages. Nonetheless nephrotoxicity and neurotoxicity pose as dire inherent side-effects in clinical trials and application of platinum therapeutics. Subsequent development has called for means to avoid diminished efficacy due to inactivation by endogenous glutathione and other complex-binding or chelating proteins. Platinum(IV) derivatives may solve issues of unintended toxicity by means of intrinsic extracellular stability, degrading to their active platinum(II) forms once internalised within a cytosol and in acidic tumour environments. Selectivity may also be gained by the axial/apical coordination of ligands that typically bind to receptors that are overexpressed in certain tumours, such as modified-estrogen ligands. The development of platinum complexes has required an in-depth understanding of their DNA-binding interactions in order to facilitate further structural modification without loss of effective function for their eventual application as chemotherapeutics. Although platinum complexes are the focus of this chapter, some other metal complexes that interact with nucleic acids, such as ruthenium, iridium, osmium, iron, copper, titanium, vanadium gold and silver, are discussed.