Chimie combinatoire dynamique

Résumé

vignette|Un exemple précoce de la chimie combinatoire dynamique en synthèse organique. Sanders et al. utilisé DCC pour générer des macrocycles dérivés de stéroïdes, capables d'interconversion par transestérification. Par définition moderne, la Chimie combinatoire dynamique (CDC) également connue sous le nom de chimie dynamique constitutionnelle (CDC) est une méthode pour faciliter la génération de molécules de nouvelle génération formées par liaisons réversibles de blocs de construction simples sous contrôle thermodynamique. Ce principe est connu pour sélectionner le produit le plus thermodynamiquement stable à partir d'un mélange à l'équilibre constitué d'un certain nombre de composants, un concept couramment utilisé en chimie de synthèse pour contrôler la sélectivité de la réaction. Structure La bibliothèque de ces blocs de construction à conversion réversible est appelée bibliothèque combinatoire dynamique (DCL) . Tous les constituants d'un DCL sont en équilibre et leu

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https://fr.wikipedia.org/wiki/Chimie_combinatoire_dynamique

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Multicomponent chemosensors were prepared by mixing the rhodium(III) complex [(η5-C5Me5)RhCl 2]2, nickel(II) chloride and/or copper(II) chloride with commercially available dyes in buffered aqueous solution. The sensors were used to detect various biomolecules, which interact with the components of the sensing ensemble and alter the composition, and hence the color of the sample. The sensors were analyzed by UV/Vis spectroscopy. A mixture of [(η5-C5Me5)RhCl 2]2, three dyes and pyrophosphate was employed to determine in retrospect the time at which the target molecules ADP and ATP were added to the sensing ensemble. An artificial neural network was used to correlate absorbance data with analyte addition times. Dynamic combinatorial libraries of metal-dye complexes prepared from NiCl2, CuCl2 and three dyes were used to distinguish between mixtures of the peptide hormones angiotensin I and angiotensin II. The discriminative power of the sensor was increased by analyzing samples in a time-resolved fashion. Nine primary amines were identified in a sensing ensemble, where amines were first combined with pyridine-2-aldehyde in the presence of NiCl2 or CuCl2, in order to obtain metal-stabilized imine mixtures. A colorimetric output was generated by adding a dye. In an approach to sense conventional sugars in an indicator displacement assay, sugars were transformed in situ into sugar imines prior to the sensing experiment.

EPFL2010

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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

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Olfaction, the detection of odorous chemicals in the environment, is one of the oldest mammalian sensory systems and involves large number (up to 1000) of distinct G protein coupled olfactory receptors (OR). The chemical interaction of volatile molecules with specific ORs marks the primary step in odor perception and is of critical importance for elucidating the molecular basis of detecting and discriminating thousands of odorous chemicals. Despite the fact that a number of putative ORs have been cloned, only limited progress has been made in assigning odorant molecules to specific receptors. Furthermore, the analysis of OR–ligand interactions at a cellular level is complicated by combinatorial recognition principles and thus requires large scale odorant and receptor screening to establish receptor-specific ligand profiles. Described herein are efforts towards the development of reliable and efficient assays for detecting and quantifying the responses of heterologously expressed ORs to odorants. Three strategies were employed for the optical or electrophysiological detection of ORs responses with functional assays in HEK293 cells. In two approaches, OR activation was monitored via the endogenous cAMP pathway, which was coupled either to the cAMP response element-mediated expression of different reporter genes, or to a cyclic nucleotide gated ion channel. In a third approach, OR activation was measured using Ca2+ imaging in the presence of a promiscuous Gαq protein. ORs of different species were then functionally analyzed using the different assays. A library of 250 odorant compounds representative of the chemical functional groups relevant in perfumery was screened; 16 novel specific ligands for the mouse eugenol odorant receptor (EGOR) were identified. Ten of these compounds are structurally unrelated to previously identified ligands and thus provide an extended molecular basis for describing the ligand-specificity and selectivity of EGOR in new detail. Interestingly, some ORs exhibited odorant responses in the cAMP-based assays, but not in Ca2+ imaging assays and vice-versa, which indicates a possible preferential OR coupling to specific G proteins. Such preferential coupling might be dependent on the cell type or influenced by specific odorant molecules and could potentially increase the complexity in odorantmediated signaling. A second part of this thesis describes investigations into other potential activities of odorants apart from their role in olfaction. An odorant compound library was screened to determine possible xenoestrogenic activity on human ERα expressed in cultured mammalian cells. An image-based assay to observe the nuclear redistribution processes of a functional YFP-ERα fluorescent chimera allowed the identification of seven odorant molecules that interact with the receptor. As the optical detection of YFP-ERα redistribution processes did not distinguish between agonistic and antagonistic effects, we tested the active substances in a reporter assay using luciferase under transcription control of two estrogen response elements (ERE). Two active odorants identified in the screening exhibited agonist activity as indicated by a dose-dependent activation of ERα mediated transcription of the luciferase reporter gene.

EPFL2007

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EPFL2007