Herein we provide an accessible account of molecular methods to probe inorganic–nucleic acid interactions. Techniques are described using copper(ii) and platinum(ii) complexes prepared in our laboratories.

This tutorial review summarizes chemical, biophysical and cellular biological properties of formally substitution-inert “non-covalent” polynuclear platinum complexes (PPCs). We demonstrate how modulation of the pharmacological factors affecting platinum compound cytotoxicity such as cellular accumulation, reactivity toward extracellular and intracellular sulfur–ligand nucleophiles and consequences of DNA binding is achieved to afford a profile of biological activity distinct from that of covalently-binding agents. The DNA binding of substitution-inert complexes is achieved by molecular recognition through minor groove spanning and backbone tracking of the phosphate clamp. In this situation, the square-planar tetra-am(m)ine Pt(II) coordination units hydrogen bond to phosphate oxygen OP atoms to form bidentate N–O–N motifs. The modular nature of the polynuclear compounds results in high-affinity binding to DNA and very efficient nuclear condensation. These combined effects distinguish the phosphate clamp as a third mode of ligand–DNA binding, discrete from intercalation and minor-groove binding. The cellular consequences mirror those of the biophysical studies and a significant portion of nuclear DNA is compacted, a unique effect different from mitosis, senescence or apoptosis. Substitution-inert PPCs display cytotoxicity similar to cisplatin in a wide range of cell lines, and sensitivity is indifferent to p53 status. Cellular accumulation is mediated through binding to heparan sulfate proteoglycans (HSPG) allowing for possibilities of tumor selectivity as well as disruption of HSPG function, opening new targets for platinum antitumor agents. The combined properties show that covalently-binding chemotypes are not the unique arbiters of cytotoxicity and antitumor activity and meaningful antitumor profiles can be achieved even in the absence of Pt–DNA bond formation. These dual properties make the substitution-inert compounds a unique class of inherently dual-action anti-cancer agents.

Zinc finger reactions with inorganic ions and coordination compounds are as diverse as the zinc fingers themselves. Use of metal ions such as Co2+ and

Polynuclear platinum agents are a structurally unique class of anti-cancer drugs, distinct from the cisplatin family. To describe the chemistry and biology of this class, it was necessary to challenge the accepted paradigms for the structure–activity relationships; design new chemotypes and delineate the structures and consequences of their DNA binding modes. This article summarizes the structural changes induced in DNA by both covalent (bond-forming) and non-covalent (ligand recognition) adducts. Solution (Nuclear Magnetic Resonance), solid state (crystallography) and gas-phase (Electrospray Ionization Mass Spectrometry) techniques have all been used to describe the new DNA structures along with molecular biological techniques. The combined approaches allow molecular description of hitherto unobserved adducts such as long-range major-groove interstrand crosslinks; directional isomers on DNA and a third class of ligand–DNA binding, the phosphate clamp. The phosphate recognition is distinct from ‘‘classic’’ minor-groove recognition or intercalation.

Simultaneous multi-element imaging using NanoSIMS (nano-scale secondary ion mass spectrometry), exploiting the novel combination of ¹⁹⁵Pt and ¹⁵N in platinum-am(m)ine antitumour drugs, provides information on the internalisation and subcellular localisation of both metal and ligands, and allows identification of ligand exchange.