Metal-based Chemosensors for Carbohydrates and Biologically Important Ligands

Chemosensors based on indicator displacement were developed for the optical detection of different analytes in aqueous solution. The sensing of carbohydrates, including glucose, in aqueous solution at pH 7.4 was achieved by a fluorescent indicator displacement assay (IDA) based on a palladium complex. The assay is easy to perform as it just requires mixing of a commercially available dye and a simple Pd complex. The sensitivity of the assay is similar to what is typically found for boronic acid-based systems, but its selectivity profile towards different carbohydrates is quite distinct. Furthermore the same complex was employed for the successful differentiation of various diols. A palladium-based sensor is a novelty as almost all carbohydrate sensors exclusively utilize boronic acids as binding site. Various palladium complexes were evaluated and the usability for carbohydrate sensing was found to be strongly dependent on the ligands. Ruthenium-arene complexes are known to have potent anticancer properties. There is an interest in a quick and simple method to give information about the stability towards ligand exchange of these complexes in aqueous solutions. Indicator displacement assays, which can give information about the binding strength of different ligands to a ruthenium-arene complex, were investigated in water at pH 7.4. Various biomolecules (different amino acids, maltol etc.) could be differentiated by a colorimetric (naked eye) IDA. Additionally, a correlation between the binding strength of the bidentate ligand and the amount of indicator displaced was found. Matrix metalloproteinase (MMPs) are endoproteinases and their dysfunction can result in various health problems (e.g. arthritis). In order to provide a quick and simple tool for the evaluation of new MMP inhibitors, colorimetric IDAs were developed. For calibration of the system, MMP inhibitors were synthesized and their IC50 values for different MMP isoforms determined. Although the new MMP inhibitors have very similar structures a differentiation by an indicator displacement array was achieved. The IC50 values were, with a couple exceptions, rather high and similar. None of the new MMP inhibitors exhibited specific inhibition of one of the studied MMP isoforms.

A Starburst-Shaped Heterometallic Compound Incorporating Six Densely Packed Gd3+ Ions

Alain Borel, Eva Jakab Toth, Joao Bruno Livramento Fig., André Merbach

The heterotritopic ligand [bpy(DTTA)2]8- has two diethylenediamine-tetraacetate units for selective lanthanide(III) coordination and one bipyridine function for selective FeII coordination. In aqueous solution and in the presence of these metals, the ligand is capable of self-assembly to form a rigid supramolecular metallostar structure, {Fe[Gd2bpy(DTTA)2(H2O)4]3}4-. We report here the physicochemical characterization of the dinuclear complex [Gd2bpy(DTTA)2(H2O)4]2- and the metallostar {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- with regard to potential MRI contrast agent applications. A combination of pH potentiometry and 1H NMR spectroscopy has been used to determine protonation constants for the ligand [bpy(DTTA)2]8- and for the complexes [Fe{bpy(DTTA)2}3]2- and [Y2bpy(DTTA)2]2-. In addition, stability constants have been measured for the dinuclear chelates [M2bpy(DTTA)2]n- formed with M = Gd3+ and Zn2+ (log KGdL = 18.2; log KZnL = 18.0; log KZnHL = 3.4). A multiple field, variable-temperature 17O NMR and proton relaxivity study on [Gd2bpy(DTTA)2(H2O)4]2- and {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- yielded the parameters for water exchange and the rotational dynamics. The 17O chemical shifts are indicative of bishydration of the lanthanide ion. The exchange rates of the two inner-sphere water molecules are very similar in the dinuclear [Gd2bpy(DTTA)2(H2O)4]2- and in the metallostar (kex298 = 8.1+/-0.3 x 10^6 and 7.4+/-0.2 x 10^6 s-1, respectively), and are comparable to kex298 for similar GdIII poly(amino carboxylates). The rotational dynamics of the metallostar has been described by means of the Lipari-Szabo approach, which involves separating global and local motions. The difference between the local and global rotational correlation times, lO298 = 190�15 ps and gO298 = 930+/-50 ps, respectively, shows that the metallostar is not completely rigid. However, the relatively high value of S2 = 0.60+/-0.04, describing the restriction of the local motions with regard to the global one, points to a limited flexibility compared with previously reported macromolecules such as dendrimers. As a result of the two inner-sphere water molecules, with their near-optimal exchange rate, and the limited flexibility, the metallostar has a remarkable molar proton relaxivity, particularly at high magnetic fields (r1 = 33.2 and 16.4 mM-1 s-1 at 60 and 200 MHz, respectively, at 25 �C). It packs six efficiently relaxing GdIII ions into a small molecular space, which leads, to the best of our knowledge, to the highest relaxivity per molecular mass ever reported for a GdIII complex. The [bpy(DTTA)2]8- ligand is also a prime candidate as a terminal ligand for constructing larger sized, FeII (or RuII)-based metallostars or metallodendrimers loaded with GdIII on the surface.

2006

Metal-based chemosensors for amino acids, peptides, and nucleotides

Andrey Buryak

An organometallic 4d transition metal complex [CpRhCl2]2, together with commercially available dyes, was used to construct indicator displacement assays (IDAs) for the detection of peptides, amino acids, and nucleotides. The combination of the CpRh complex with the dye azophloxine was found to form a chemosensing ensemble for the sequence-selective detection of histidine- and methionine-containing peptides in water at neutral pH. A strong interaction of the rhodium complex with peptides bearing histidine or methionine residue in the position 1 or 2 allowed to detect these peptides down to a concentration of 0.3 µM. The same organometallic complex and three commercially available dyes were employed to compose an array of IDA chemosensors for the detection of natural amino acids. We found that the variation of the pH can effectively be used to modulate the selectivity of an IDA sensor. An excellent discrimination of 20 amino acids was achieved. The combination of [Cp*RhCl2]2 with the dyes gallocyanine, evans blue, and mordant yellow 10 forms a multicomponent indicator displacement assay (MIDA), which can be used to sense low millimolar concentrations of nucleotides and the pyrophosphate anion in buffered aqueous solution. Moreover, the MIDA allows to simultaneously determine the concentrations of adenosine triphosphate and pyrophosphate/cyclic adenosine monophosphate with a single UV-Vis measurement. In the second part of our work we investigated whether dynamic combinatorial libraries (DCLs) can be used for sensing purposes. We found that the dyes arsenazo I, methylcalcein blue, and glycine cresol red, in combination with the metal salts CuCl2 and NiCl2, form a DCL of differently colored metal-dye complexes. The addition of an analyte able to interact with a member(s) of such a library, results in a re-equilibraion easily detectable by UV-Vis spectroscopy. Using dipeptides as analytes we demonstrated that this way of sensing is very effective – even closely related peptides such as regio- (Ala-Phe vs. Phe-Ala) and stereo- (Phe-Ala vs. D-Phe-Ala) isomers can easily be discriminated. Additionally, we found that the identity of the best sensor depends on the problem to be addressed.

EPFL2007

Metal-based chemosensors for amino acids, peptides, and nucleotides

Andrey Buryak

EPFL2007

A Starburst-Shaped Heterometallic Compound Incorporating Six Densely Packed Gd3+ Ions

Alain Borel, Eva Jakab Toth, Joao Bruno Livramento Fig., André Merbach

2006