Metallo-intercalators and metallo-insertors

Since the elucidation of the structure of double helical DNA, the construction of small molecules that recognize and react at specific DNA sites has been an area of considerable interest. In particular, the study of transition metal complexes that bind DNA with specificity has been a burgeoning field. This growth has been due in large part to the useful properties of metal complexes, which possess a wide array of photophysical attributes and allow for the modular assembly of an ensemble of recognition elements. Here we review recent experiments in our laboratory aimed at the design and study of octahedral metal complexes that bind DNA non-covalently and target reactions to specific sites. Emphasis is placed both on the variety of methods employed to confer site-specificity and upon the many applications for these complexes. Particular attention is given to the family of complexes recently designed that target single base mismatches in duplex DNA through metallo-insertion

Synthetic metallomolecules as agents for the control of DNA structure

This tutorial review summarises B-DNA structure and metallomolecule binding modes and illustrates some DNA structures induced by molecules containing metallic cations. The effects of aquated metal ions, cobalt amines, ruthenium octahedral metal complexes, metallohelicates and platinum complexes such as cis-platin are discussed alongside the techniques of NMR, X-ray crystallography, gel electrophoresis, circular dichroism, linear dichroism and molecular dynamics. The review will be of interest to people interested in both DNA structure and roles of metallomolecules in biological systems

Unusual DNA binding modes for metal anticancer complexes

DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes

The path for metal complexes to a DNA target

The discovery of cisplatin as a therapeutic agent stimulated a new era in the application of transition metal complexes for therapeutic design. Here we describe recent results on a variety of transition metal complexes targeted to DNA to illustrate many of the issues involved in new therapeutic design. We describe first structural studies of complexes bound covalently and non-covalently to DNA to identify potential lesions within the cell. We then review the biological fates of these complexes, illustrating the key elements in obtaining potent activity, the importance of uptake and subcellular localization of the complexes, as well as the techniques used to delineate these characteristics. Genomic DNA provides a challenging but valuable target for new transition metal-based therapeutics

Dynamics of Metal Centers Monitored by Nuclear Inelastic Scattering

Nuclear inelastic scattering of synchrotron radiation has been used now since 10 years as a tool for vibrational spectroscopy. This method has turned out especially useful in case of large molecules that contain a M\"ossbauer active metal center. Recent applications to iron-sulfur proteins, to iron(II) spin crossover complexes and to tin-DNA complexes are discussed. Special emphasis is given to the combination of nuclear inelastic scattering and density functional calculations

Photoactivatable metal complexes : from theory to applications in biotechnology and medicine

This short review highlights some of the exciting new experimental and theoretical developments in the field of photoactivatable metal complexes and their applications in biotechnology and medicine. The examples chosen are based on some of the presentations at the Royal Society Discussion Meeting in June 2012, many of which are featured in more detail in other articles in this issue. This is a young field. Even the photochemistry of well-known systems such as metal–carbonyl complexes is still being elucidated. Striking are the recent developments in theory and computation (e.g. time-dependent density functional theory) and in ultrafast-pulsed radiation techniques which allow photochemical reactions to be followed and their mechanisms to be revealed on picosecond/nanosecond time scales. Not only do some metal complexes (e.g. those of Ru and Ir) possess favourable emission properties which allow functional imaging of cells and tissues (e.g. DNA interactions), but metal complexes can also provide spatially controlled photorelease of bioactive small molecules (e.g. CO and NO)—a novel strategy for site-directed therapy. This extends to cancer therapy, where metal-based precursors offer the prospect of generating excited-state drugs with new mechanisms of action that complement and augment those of current organic photosensitizers

NMR evidence for specific intercalation of Δ-rh(phen)_2phi^(3+) in [d(GTCGAC)_2]

The anchoring of metal complexes in the major groove of DNA through intercalation has been increasingly useful in the shape-selective design of novel metal complexes which bind DNA with high sequence-selectivity. Toward that goal, direct structural information regarding this intercalative interaction is essential. Phenanthrenequinone diimine (phi) complexes of Rh(III) bind avidly (K_b 1 ≥ 10^7) to DNA by intercalation in the major groove. Here we report the first ^1H-NMR studies of Δ-rh(phen)_2phi^(3+) bound to an oligonucleotide. These studies provide direct structural evidence for specific intercalation by this octahedral complex in the major groove of DNA

Platinated DNA oligonucleotides: new probes forming ultrastable conjugates with graphene oxide

Metal containing polymers have expanded the property of polymers by involving covalently associated metal complexes. DNA is a special block copolymer. While metal ions are known to influence DNA, little is explored on its polymer property when strong metal complexes are associated. In this work, we study cisplatin modified DNA as a new polymer and probe. Out of the complexes formed between cisplatin–A15, HAuCl4–A15, Hg2+–T15 and Ag+–C15, only the cisplatin adduct is stable under the denaturing gel electrophoresis condition. Each Pt–nucleobase bond gives a positive charge and thus makes DNA a zwitterionic polymer. This allows ultrafast adsorption of DNA by graphene oxide (GO) and the adsorbed complex is highly stable. Non-specific DNA, protein, surfactants and thiolated compounds cannot displace platinated DNA from GO, while non-modified DNA is easily displaced in most cases. The stable GO/DNA conjugate is further tested for surface hybridization. This is the first demonstration of using metallated DNA as a polymeric material for interfacing with nanoscale materials.University of Waterloo Canadian 95 Foundation for Innovation Natural Sciences and Engineering Research Council and the Early Researcher Award Ministry of Research, Innovation and Science of Ontari

Metal complexes for DNA-mediated charge transport

In all organisms, oxidation threatens the integrity of the genome. DNA-mediated charge transport (CT) may play an important role in the generation and repair of this oxidative damage. In studies involving long-range CT from intercalating Ru and Rh complexes to 5′-GG-3′ sites, we have examined the efficiency of CT as a function of distance, temperature, and the electronic coupling of metal oxidants bound to the base stack. Most striking is the shallow distance dependence and the sensitivity of DNA CT to how the metal complexes are stacked in the helix. Experiments with cyclopropylamine-modified bases have revealed that charge occupation occurs at all sites along the bridge. Using Ir complexes, we have seen that the process of DNA-mediated reduction is very similar to that of DNA-mediated oxidation. Studies involving metalloproteins have, furthermore, shown that their redox activity is DNA-dependent and can be DNA-mediated. Long range DNA-mediated CT can facilitate the oxidation of DNA-bound base excision repair proteins to initiate a redox-active search for DNA lesions. DNA CT can also activate the transcription factor SoxR, triggering a cellular response to oxidative stress. Indeed, these studies show that within the cell, redox-active proteins may utilize the same chemistry as that of synthetic metal complexes in vitro, and these proteins may harness DNA-mediated CT to reduce damage to the genome and regulate cellular processes

Counterion Effects on Nano-confined Metal-Drug-DNA Complexes

We have explored morphology of DNA molecules bound with Cu-complexes of piroxicam molecules, a non-steroidal anti-inflammatory drug (NSAID), under one-dimensional confinement of thin films and have studied the effect of counterions present in a buffer. X-ray reflectivity at and away from the Cu K absorption edge and atomic force microscopy studies reveal that confinement segregates the drug molecules preferentially in a top layer of the DNA film, and counterions enhance this segregation