New ternary water-soluble support from self-assembly of ß-cyclodextrin-ionic liquid and an anionic polymer for a dialysis device.

We developed a new hybrid material resulting from an innovative supramolecular tripartite association between an ionic liquid covalently immobilized on primary ß-cyclodextrins rim and an anionic water-soluble polymer. Two hydrophilic ternary complexes based on native and permethylated ß-cyclodextrins substituted with an ionic liquid and immobilized on poly(styrene sulfonate) (CD-IL+PSS- and CD(OMe)IL+PSS-) were obtained by simple dialysis with a cyclodextrin maximal grafting rate of 25% and 20% on the polymer, respectively. These polyelectrolytes are based on electrostatic interactions between the opposite charges of the imidazolium cation of the ionic liquid and the poly(styrene sulfonate) anion. The inclusion properties of the free cavities of the cyclodextrins and the synergic effect of the polymeric matrix were studied with three reference guests such as phenolphthalein, p-nitrophenol, and 2-anilinonaphthalene-6-sulfonic acid using UV-visible, fluorescent, and NMR spectroscopies. The support has been applied successfully in dialysis device to extract and concentrated aromatic model molecule. This simple and flexible synthetic strategy opens the way to new hybrid materials useful for fast and low-cost ecofriendly extraction techniques relevant for green analytical chemistry.

FRET-Based In-Cell Detection of Highly Selective Supramolecular Complexes of meso-Tetraarylporphyrin with Peptide/BODIPY-Modified Per-O-Methyl-ß-Cyclodextrins.

Artificial supramolecular systems capable of self-assembly and that precisely function in biological media are in high demand. Herein, we demonstrate a highly specific host-guest-pair system that functions in living cells. A per-O-methyl-ß-cyclodextrin derivative (R8-B-CDMe ) bearing both an octaarginine peptide chain and a BODIPY dye was synthesized as a fluorescent intracellular delivery tool. R8-B-CDMe was efficiently taken up by HeLa cells through both endocytosis and direct transmembrane pathways. R8-B-CDMe formed a 2 : 1 inclusion complex with tetrakis(4-sulfonatophenyl)porphyrin (TPPS) as a guest molecule in water, from which fluorescence resonance energy transfer (FRET) from R8-B-CDMe to TPPS was observed. The FRET phenomenon was clearly detected in living cells using confocal microscopy techniques, which revealed that the formed supramolecular R8-B-CDMe /TPPS complex was maintained within the cells. The R8-B-CDMe cytotoxicity assay revealed that the addition of TPPS counteracts the strong cytotoxicity (IC50 =16 µM) of the CD cavity due to complexation within the cells. A series of experiments demonstrated the bio-orthogonality of the supramolecular per-O-methyl-ß-CD/tetraarylporphyrin host-guest pair in living cells.

Cyclodextrins: promising scaffolds for MRI contrast agents.

Magnetic resonance imaging (MRI) is a powerful tool for non-invasive, high-resolution three-dimensional medical imaging of anatomical structures such as organs and tissues. The use of contrast agents based on gadolinium chelates started in 1988 to improve the quality of the image, since researchers and industry focused their attention on the development of more efficient and stable structures. This review is about the state of the art of MRI contrast agents based on cyclodextrin scaffolds. Chemical engineering strategies are herein reported including host-guest inclusion complexation and covalent linkages. It also offers descriptions of the MRI properties and in vitro and in vivo biomedical applications of these emerging macrostructures. It highlights that these supramolecular associations can improve the image contrast, the sensitivity, and the efficiency of MRI diagnosis by targeting cancer tumors and other diseases with success proving the great potential of this natural macrocycle.

Synthesis and Unprecedented Complexation Properties of ß-Cyclodextrin-Based Ligand for Lanthanide Ions.

Here, we report the synthesis and detailed studies on the coordination chemistry of a novel chemically modified polyaminocarboxylate (5) based on ß-cyclodextrin (CD) scaffold for lanthanides. The target ligand is prepared in a highly efficient manner (seven total steps) from ß-CD using the readily available iminodiacetic acid as a starting material. A propargyl group is attached to the iminodiacetate via N-alkylation, and the obtained derivative is efficiently conjugated to the ß-CD scaffold via the copper(I)-mediated 1,3-dipolar cycloaddition. The generated 1,2,3-triazolmethyl residues advantageously provide a competent chelating group while displacing the metal coordination center away from the primary rim of ß-CD, to afford the required conformational flexibility. The functional groups from each of the two adjacent glucopyranosyl units of ß-CD complete a uniquely created octavalent coordination sphere for lanthanides while still sparing one site for dynamic water coordination. To help study the coordination chemistry of CD ligand 5, we also design a relevant maltoside ligand 6, which faithfully represents one submetal-binding section of ligand 5. Thanks to HRMS and NMR studies, we successfully elucidate the coordination chemistries of synthesized ligands. The octavalent coordination sphere of ligand 5 shows strong binding affinity to lanthanides. By potentiometric titration experiments, ligand 5 is found to bind gadolinium(III), forming 1:1, 1:2, and 1:3 multinuclear complexes with lanthanides, thus possessing great capacity for catalyzing the dynamic water-exchange. Further NMR studies also reveal that the formed ligand 5/Gd(III) complexes show significantly better abilities to alter T1 relaxivities of coordinated water than DOTA-Gd(III) and also some of the synthetic CD probes reported in the literature.

Structure-efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds.

New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents. The degradation efficiency was found to be dependent on the relative position of the heterocycle towards the reactive group as well as on the nature of the organophosphorus derivative.

Ionic liquids and cyclodextrin inclusion complexes: limitation of the affinity capillary electrophoresis technique.

The state of the art of inclusion complex formation between cyclodextrins and ionic liquids is reported. Mechanisms, stoichiometries, and binding constants are summarized and classified by anion. We investigated the supramolecular interactions between the ß-cyclodextrin cavity and six ionic liquids based on 1-dodecyl-3-methylimidazolium by affinity capillary electrophoresis and compared the results with those obtained by isothermal titration calorimetry. We show that the presence of basic or acidic buffers leads to a metathesis reaction, underlining the limitation of the affinity capillary electrophoresis technique.

Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds.

The aim of this review is to provide an update on the current use of cyclodextrins against organophosphorus compound intoxications. Organophosphorus pesticides and nerve agents play a determinant role in the inhibition of cholinesterases. The cyclic structure of cyclodextrins and their toroidal shape are perfectly suitable to design new chemical scavengers able to trap and hydrolyze the organophosphorus compounds before they reach their biological target.

Structure-Binding Effects: Comparative Binding of 2-Anilino-6-naphthalenesulfonate by a Series of Alkyl- and Hydroxyalkyl-Substituted ß-Cyclodextrins.

Cyclodextrins (CDs) are the most widely used organic hosts for the inclusion of guest molecules. CDs can be readily modified through substitutions of the hydroxyl groups, and these modified CDs can have different host binding properties compared to those of parent CDs. However, only relatively few systematic studies of the effects of chemical substitution on CD binding ability have been reported thus far. In this paper, we report the study of the binding properties of five different analytically pure modified ß-cyclodextrin (ß-CD) hosts (substituted with alkyl and/or hydroxyalkyl groups) with 2-anilino-6-naphthalenesulfonate (2,6-ANS) as guest. Binding constants for the formation of the inclusion complex between 2,6-ANS and each CD were determined using both fluorescence spectroscopy and capillary electrophoresis. Addition of modified CDs to an aqueous solution of 2,6-ANS resulted in significant enhancement of the fluorescence intensity of 2,6-ANS, as well as a significant spectral blue shift, indicative of inclusion. Inclusion of 2,6-ANS within the CD cavity was confirmed by NMR spectroscopy. Substitution at position 3 decreased the magnitude of the binding constants, while alkyl or hydroxylalkyl substitution of the primary hydroxyl at position 6 increased the magnitude of the binding constant in all cases, in relation with increasing length of the alkyl chain linker. In addition, binding constants decreased with solvent polarity when increasing amounts of methanol were added. Structure-binding correlations for CDs based on these binding constant results are presented and discussed.

New modified ß-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (I). Synthesis and preliminary screening: evaluation of the detoxification using a half-quantitative enzymatic assay.

Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on ß-cyclodextrin displayed promising results, but further investigations have to be performed to evaluate the possibility of application of substituted cyclodextrins as potential detoxification agents. Herein, five new cyclodextrins scavengers were synthesized. New optimal conditions for regioselectively monosubstitution of ß-cyclodextrin at O-2 position were then studied to access to key intermediates. After these optimizations, a new series of three permethylated derivatives was developed, and two compounds bearing an α-nucleophilic group via a three carbon atoms linker were prepared. The ability of these five scavengers to detoxify nerve agents (cyclosarin, soman, tabun and VX) was evaluated by a semi-quantitative biological assay. All the modified cyclodextrins significantly decreased the inhibitory effect of chemical warfare G agents on acetylcholinesterase activity. For this purpose, we showed that the specific interactions between the organophosphorus compound and the oligosaccharidic moiety of the scavenger played a pivotal role in the detoxification process.

Chiral discrimination in host-guest supramolecular complexes. Understanding enantioselectivity and solid solution behaviors by using spectroscopic methods and chemical sensors.

Diastereomeric host-guest associations formed between permethylated-beta-cyclodextrin (TMbeta-Cd) and the two enantiomers of p-bromophenylethanol (pBrPE) were characterized in aqueous solution by NMR spectroscopy, revealing similar inclusion geometries and weak binding constants, whatever the guest configuration. These features were confirmed by hydrogenation experiments, and do not allow to account for the ability of TMbeta-Cd to resolve racemic pBrPE by successive crystallizations [Grandeury, A.; Petit, S.; Gouhier, G.; Agasse, V.; Coquerel, G. Tetrahedron: Asymmetry 2003, 14, 2143-2152]. The analysis, by means of solid-state NMR, oxidation experiments, and solubility measurements, of the two crystalline phases containing known proportions of guest enantiomers revealed identical inclusion geometries in a given phase, irrespective of the enantiomeric composition. The corresponding solid solutions were further characterized by the determination of an isothermal section (40 degrees C) in the relevant ternary phase diagram. It appears from all these data that chiral resolution mechanisms in this system can only be envisaged in terms of nucleation conditions of each crystal form (with its specific inclusion geometry) and enantiomeric recognition at crystal solution interfaces during the growth of each crystal packing.

Nucleotides and nucleic acids: a source of inspiration for the development of new, phosphorus-centered functional groups.

Synthetic methodologies aiming at the creation of new phosphorus-centered functional groups are reported, as well as applications to the field of nucleotide chemistry. Thus, difluorophosphonothioate-based, ionic reagents 3b and 3d are shown to allow the stereocontrolled and efficient synthesis of phosphonodifluoromethyl analogues of nucleoside-3'-phosphates. An alternate, radical approach describes the use of hypophosphorous acid to stereoselectively link two furanosyl units in positions 3 and 5, and to provide an access to alpha,alpha-difluoro-H-phosphinates. These intermediates are shown to be precursors to the corresponding fluorinated phosphonic acids, phosphonothioic acids and variously substituted phosphinates.

Phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals. Generation and addition onto alkenes and alkynes.

[reaction: see text] Selanylated difluoromethylphosphonates and difluoromethylphosphonothioates are good precursors to phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals, respectively. When generated in the presence of alkenes and a hydrogen donor, the corresponding alpha,alpha-difluorinated alkylphosphonates or alkylphosphonothioates are produced in fair to good yields. The use of alkynes results in the formation of alpha,alpha-difluorinated allyl derivatives in useful yields. The presence of the sulfur atom in phosphonothiodifluoromethyl radicals usually translates into higher isolated yields.

New synthesis of (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one under stereospecific constraints induced by host-guest interactions.

A selective, efficient, and fast access to (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one (BCBCH), precursor of the synthetic antagonist of tissue-plasminogen activator (t-PA), is reported using a solid/solid aldolisation-crotonisation reaction on a supramolecular complex under microwave irradiation. The underlying mechanism is investigated from the crystal structure of the intermediate host-guest complex formed between permethylated gamma-cyclodextrin and (Z)-2-(4-cyanobenzylidene)cycloheptan-1-one.

Development of cross-linked polystyrene-supported chiral amines featuring a fluorinated linker for gel-phase 19F NMR spectrometry monitoring of reactions.

Ten cross-linked polystyrene-supported, protected chiral amines featuring both a spacer, comprising from 5 to 15 atoms, and a fluorinated linker have been successfully prepared. The development of the monitoring technique by gel-phase 19F NMR spectrometry on cross-linked polystyrene derivatives proved to be of high value in four steps of the process, as shown by the comparison of data gathered from both a classic NMR spectrometer and elemental analysis. Gel-phase 19F NMR spectrometry, thus, constitutes a useful technique that complements IR and 13C NMR spectrometries for the qualitative monitoring of reactions. In addition, quantitative determination of the conversion in a given transformation is possible, provided that 19F chemical shifts of the substrate and the product be different enough (Deltadelta>base width), as illustrated by the Mitsunobu coupling process (16-->17). The technique is nondestructive, and the samples used to monitor the reactions may be returned to the reaction medium. Deprotection of the above amines was achieved and furnished eight of the final resins in good to acceptable purity for future applications.

The preparation of new phosphorus-centered functional groups for modified oligonucleotides and other natural phosphates.

Efforts to develop synthetic methodologies allowing the preparation of alpha,alpha- difluorophosphonothioates, alpha,alpha-difluorophosphonodithioates, alpha,alpha-difluorophosphono- trithioates, and alpha,alpha-difluorophosphinates are reviewed in the light of applications in the field of modified oligonucleotides and cyclitol phosphates. Two successful approaches have been developed, based either on the addition of phosphorus-centered radicals onto gem-difluoroalkenes or on a process involving the addition of lithiodifluorophosphono- thioates 91 onto a ketone and the subsequent deoxygenation reaction of the adduct. The radical route successfully developed a practical route to alpha,alpha-difluoro-H-phosphinates which proved to be useful intermediates to a variety of phosphate isosters. The ionic route led to the first preparation of phosphonodifluoromethyl analogues of nucleoside- 3'-phosphates.

Phosphonyl, phosphonothioyl, phosphonodithioyl, and phosphonotrithioyl radicals: generation and study of their addition onto alkenes.

The treatment of benzyl dialkyl phosphites and dithiophosphites with benzeneselanyl chloride generates an Arbuzov-type transformation leading to the dialkyl selenophosphates 19a and 19b and to selenophosphorodithioates 21a and 21b. Interaction of these substrates with Lawesson's reagent yields the corresponding selenophosphorothioates 20a and 20b and the selenophosphorotrithioates 22a and 22b. When treated with a radical initiator in the presence of a hydrogen donor and an alkene, all eight phosphorus(V) precursors undergo homolytic cleavage of the P-Se bond to generate the phosphonyl, phosphonothioyl, phosphonodithioyl, or phosphonotrithioyl radicals. Most of these are shown to add onto electron-rich and electron-poor alkenes to deliver the expected adducts in fair to excellent yields. Cyclic precursor 19b displays peculiar behavior and, under the reaction conditions, produces only the corresponding cyclic phosphite. Application of this radical chain process is carried out on furanosyl 3-exo-methylene derivative 37 to diastereoselectively furnish five new 3-phosphonomethyl-, 3-phosphonothiomethyl-, and 3-phosphonodithiomethyl-3-deoxofuranoses 38a-c and 38f,g. The possibility of conducting tandem processes is also discussed through experiments involving (1R)-(+)-alpha-pinene (39) and diallylamine 41.

First and efficient synthesis of phosphonodifluoromethylene analogues of nucleoside 3'-phosphates: crucial role played by sulfur in construction of the target molecules.

Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despite the obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a single example of such an analogue featuring this particular substitution pattern has so far been reported in the literature, due to synthetic problems associated with their preparation. The lithium salt of diethyl difluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-step synthesis of all five fully protected analogues of nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones. Sulfur is shown to play a crucial role in the introduction of the phosphorus-substituted difluoromethylene unit onto the furanose ring. Complete diastereoselectivity is observed in the three steps of the process requiring stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis can be carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodium salts.