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.

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A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is La, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Fe, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T) of the fluorine nuclei. The shorter T allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T/T ratio. In water, the optimal metal complexes for imaging applications are those containing Ho and Fe, and to a lesser extent Tm and Yb. Whereas T of the lanthanide complexes are little affected by blood, the T are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, Ho-DOTAm-F12, could not be detected in blood. Tm yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of Fe-DOTAm-F12 are similar in water and in blood. That complex has the highest T/T ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T/T of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

The advent of chemical tools for cellular imaging--from organic dyes to green fluorescent proteins--has revolutionized the fields of molecular biology and biochemistry. Lanthanide-based probes are a new player in this area, as the last decade has seen the emergence of the first responsive luminescent lanthanide probes specifically intended for imaging cellular processes. The potential of these probes is still undervalued by the scientific community. Indeed, this class of probes offers several advantages over organic dyes and fluorescent proteins. Their very long luminescence lifetimes enable quantitative spatial determination of the intracellular concentration of an analyte through time-gating measurements. Their emission bands are very narrow and do not overlap, enabling the simultaneous use of multiple lanthanide probes to quantitatively detect several analytes without cross-interference. Herein we describe the principles behind the development of this class of probes. Sensors for a desired analyte can be designed by rationally manipulating the parameters that influence the luminescence of lanthanide complexes. We will discuss sensors based on varying the number of inner-sphere water molecules, the distance separating the antenna from the lanthanide ion, the energies of excited states of the antenna, and PeT switches.