Metal interactions with nucleic acids

The crucial role of metal ions in biology and medicine is a subject of intense study across the globe with a thriving community and a suite of successful biennial conferences, including the International Conference on Bioinorganic Chemistry (ICBIC) that has been running for over 30 years (and will meet for the 17^th time this summer in Beijing), thriving European, Asian, and Latin American “BIC” meetings (EuroBIC, AsBIC and LaBIC), multiple US Gordon Research Conferences, and the International Symposium on Applied Bioinorganic Chemistry (meeting for the 13^th time in Galway, Ireland, this summer). The European contributions to the field have benefitted greatly from various EU-ESF COST Actions such as D39 (Metallo-drug design and Action) and CM1105 (Functional metal complexes that bind to biomolecules) that have networked key groups together and helped to nurture younger entrants into the field.

The role of metal ions in proteins/enzymes and biomimetic systems with catalytic properties have been widely explored, including in this journal, and, indeed, the molecular aspects of the field started to become clear with the structure of vitamin-B₁₂ and haemoglobin in the 1960s. But the role of metal ions and complexes in binding to nucleic acids has, comparatively, been less studied. The first boost for this area came when it was realized that the anticancer drug cisplatin, cis-diamminedichloridoplatinum(II), interacts with DNA and when structures of such adducts at atomic resolution became available. In the last decade we have seen further impetus in the sub-field as a suite of new crystal structures – notably of metal-complexes binding non-coordinatively and non-covalently to DNA and RNA – started to emerge. These have not only greatly enhanced our understanding of the way compounds can interact with nucleic acids but also started to show the range of different nucleic acid structures that might be bound and the range of different approaches to binding them. Janice Aldrich-Wright's perspective article at the opening of the issue explores some of these new developments (10.1039/C4DT02700K).

The influence of this new body of crystallographic work can be seen across the spectrum of papers that are gathered together in this special issue, with work from Per Lincoln looking in more detail at the binding of ruthenium intercalators (10.1039/C4DT02642J) and from Nick Farrell on the exciting ‘phosphate clamp’ binding motif seen with his polynuclear platinum complexes (10.1039/C4DT03237C). Non-canonical (non-duplex) DNA targets are addressed by Luigi Messori (10.1039/C4DT02698E), Genevieve Pratviel (10.1039/C4DT03631J) and Ramon Vilar (10.1039/C4DT02910K) who contribute papers on targeting DNA quadruplexes. Quadruplex recognition represents the largest current area of activity ‘beyond the duplex’, but other non-duplex targets can be just as exciting as shown by Janet Morrow's stimulating work on recognising looped out thymines in both quadruplexes and bulges (10.1039/C4DT03004D). Janet uses zinc complexes for the thymine recognition (coupled with aromatic stacking onto the thymine) and Giampaolo Barone reviews the broader area of zinc chemosensing for nucleic acid recognition in his perspective (10.1039/C4DT02881C). The theme of combining coordinative binding and aromatic stacking is seen again in Claudia Turro's contribution on photoactive dirhodium complexes that bind both coordinatively and through π-stacking to guanine following irradiation with visible light (10.1039/C4DT03119A), while dinuclear macrocylic zinc(II) complexes are used in a different way by Bernhard Spingler, who explores how to use them to induce the formation of left-handed Z-DNA (10.1039/C4DT02713B). Bernhard shows, however, that the nickel(II) and copper(II) analogues are still more potent in controlling DNA structure.

One of the main drivers for work in the field of DNA recognition had come from the potential to develop new DNA binding modes that will deliver new types of anti-cancer actions in cells and organisms beyond that demonstrated by cisplatin. Readers can see that reflected in Giovanni Natile's contribution on Kiteplatin (10.1039/C4DT01796J), Victor Brabec's (10.1039/C4DT02603A) and Dori Quiroga's (10.1039/C4DT02392G) papers on trans-platinum agents and Sue Berners-Price and Nick Farrell's paper on agents that can form two mono-functional platinum-DNA lesions (10.1039/C4DT02942A). Christian Hartinger and Paul Dyson (10.1039/C4DT02764G) seek new activity by linking a DNA-alkylator to a protein-binding ruthenium agent and demonstrate the potential to form DNA and protein cross-links which could be potent lesions in cells. Peter Sadler and Peter O'Connor have introduced Osmium compound binding to G and C bases on DNA, using high-resolution mass spectrometry (10.1039/C4DT03819C). Norah Barba Behrens (10.1039/C4DT02883J) explores the DNA lesions formed by clotrimazole bound to first-row transition-metal dications finding coiling of DNA and, with copper(II), oxidative damage.

Nevertheless the scope of the field and the drivers for the research are much broader than just anti-cancer activity and readers will see interests from DNA nanotechnology reflected in Jens Müller's contribution (10.1039/C4DT02663B), which looks at metals within the DNA as part of artificial DNA base pairs, and interests in using DNA's chiral microenvironment in a pair of papers from Gerard Roelfes (10.1039/C4DT02733G; 10.1039/C4DT02734E), who has pioneered the use of the chiral DNA grooves to host and influence the course of catalytic reactions.

A key frontier for the field is to be able to study and understand nucleic acid binding inside a cell, rather than just in a test tube, and two of the studies in this issue represent steps in that direction. Richard Keene and Grant Collins describe the use of fluorescence microscopy to study the localisation of fluorescent ruthenium agents in the cell, comparing them to other nucleic-acid binders and indicating the RNA-rich nucleolus as a target (10.1039/C4DT02575J). Vicky DeRose's elegant paper (10.1039/C4DT02649G) complements this approach, describing a platinum drug bearing an azide that can be clicked on to a fluorophore after it has bound to its biomolecular targets, opening up the potential for in cellulo visualisation of the biomolecule binding of a non-fluorescent platinum drug.

As guest editors it has been a pleasure to assist in preparing this special issue, and we would like to thank the authors for their contributions, the referees for their evaluations and referee reports, the editorial board for proposing this issue and their ongoing commitment to supporting biological inorganic chemistry, and the Dalton Transactions editorial staff for handling the manuscripts and their technical support.

We hope that the issue will serve to highlight the diversity and health of this bioinorganic subfield and bring the general readership of the journal some insight into the fascinating developments in this discipline over the last decade. We have tried to group together a modest, but representative, collection of articles from leading groups worldwide, and covering most subtopics in the area. We also trust that this special issue will serve to alert potential new authors, whether chemists or biomedical scientists, to the commitment of Dalton Transactions to support and nurture this field and highlight that Dalton Transactions is keen to receive top research papers on the interaction of metal complexes with DNA and RNA as well as in all other aspects of biological inorganic chemistry.

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