Positive variation of the MRI signal via intramolecular inclusion complexation of a C-2 functionalized ß-cyclodextrin.

The synthesis of a new contrast agent based on a ß-cyclodextrin scaffold and bearing a flexible lipophilic spacer arm on its secondary face is reported. Intermolecular host-guest inclusion complexes were known to undergo an enhancement of the contrast imaging. We extend this concept to intramolecular complexation. Inter- and intramolecular interactions are compared by NMR spectroscopy, circular dichroism and magnetic resonance imaging using hydrocinnamic acid and adamantane carboxylic acid as external guests. This positive variation of the observed relaxivity is a key element of new strategies aiming at developing smart molecular MRI probes.

[Substituted cyclodextrins: an example of biomimetic catalyzers]. / Les cyclodextrines substituées: un exemple de catalyseurs biomimétiques.

Among all molecules used to develop biomimetic catalysts, cyclodextrins are extremely attractive compounds. These oligosaccharides can form inclusion complexes with various organic substrates and in particular with organophosphorus poisons, which are widely used as chemical weapons and insecticides. Soman, a frightening neurotoxic agent, once "trapped" in the internal cavity of beta-cyclodextrin can moreover undergo the nucleophilic attack of an oligosaccharide hydroxyl group, miming the first step of the enzymatic process. Selective substitution of beta-cyclodextrin by a 2-iodosobenzoic acid derivative has enabled effective synthesis of scavangers against organophosphorus compounds. Hydrolysis trials were carried out with paraoxon, as an organophosphorus model. The OP-hydrolyzing activity could reach more than two order of magnitude compared with free 2-iodosobenzoïc acid. Nevertheless, hydrolysis of paraoxon showed saturation kinetics. Although the activity was strongly dependent on the relative position of the reactive group, these results showed the interest of a strategy, resulting in the "trapping" of the organophosphorus substrate in the internal cavity of the oligosaccharide in order to maintain it near the catalytic function.

The first 2(IB),3(IA)-heterodifunctionalized ß-cyclodextrin derivatives as artificial enzymes.

Novel 2,3-heterodisubstituted ß-cyclodextrin derivatives were designed as artificial enzymes to degrade chemical warfare agents. One of them reduced the acetylcholinesterase inhibitory potential by soman faster than its monosubstituted analog.

[Porphyrin catalysts: a tool for preparation of metabolite models]. / Les catalyseurs porphyriniques: un outil pour la préparation de modèles de métabolites.

The porphyrin complexes of manganese catalysts are biomimetic catalysts whose structural analogy with the active site of cytochrome P-450 enzymes can be used to obtain synthetic models of therapeutic agent metabolites. Mn(TDCOO)Cl, a second generation porphyrin, has proven robust enout to be used for scaled-up production in the presence of hydrogen peroxide and imidazole. For this purpose, an improvement in substrate oxidation was obtained by adjunction of formic acid to the reaction medium which preserved the cocatalyst and the catalyst. It was shown that addition of acid played an active role in the oxidation process. After this optimization, the system was used to oxidate the two enantiomers of methyloctalone, an essential chiral intermediate in the synthesis of terpenoids and steroids. The efficacy of this biomimetic method for the preparation of large amounts of oxidized chiral synthons was better than obtained with biological ex vivo pathways.

Functionalized cyclodextrins bearing an alpha nucleophile--a promising way to degrade nerve agents.

Organophosphorus nerve agents are irreversible inhibitors of acetylcholinesterase. Current treatment of nerve agent poisoning has limited efficacy and more efficient medical countermeasures need to be developed. A promising approach is to design chemical scavengers more stable during storage and less immunogenic than bioscavengers. Furthermore, they could be produced at lowest production costs. Cyclodextrins are attractive cyclic oligosaccharides that can be used to develop chemical scavengers of organophosphorus nerve agents. Their abilities to form inclusion and non-inclusion complexes with organic substrates are useful to trap chemical warfare agents. Selective introduction of an α-nucleophile residue on the secondary face of ß-cyclodextrin allowed to obtain supramolecular derivatives active against organophosphorus compounds. The degradation activity of these monosubstituted cyclodextrins was determined against paraoxon and chemical warfare agents. These tests showed that the structure of the scavengers mainly influences the interaction between the organophosphorus substrate, or its reaction products, and the cyclodextrin moiety. All the tested G-type agents were efficiently degraded. According to the binding modes of cyclosarin, some oligosaccharidic scavengers led to an enantioselective degradation of this nerve agent. These promising derivatives open the way to further investigations of new structural modifications to reach more sophisticated and efficient scavengers for prophylactic and curative medical applications.

Detoxification of nerve agents by a substituted beta-cyclodextrin: application of a modified biological assay.

Chemical warfare agents (nerve agents) are still available and present a real threat to the population. Numerous in vitro and in vivo studies showed that various nerve agents, e.g. tabun and cyclosarin, are resistant towards standard therapy with atropine and oxime. Based on these facts we applied a modified biological assay for the easy, semi-quantitative testing of the detoxifying properties of the beta-cyclodextrin derivative CD-IBA. Cyclosarin, sarin, tabun and VX were incubated with CD-IBA for 1-50 min at 37 degrees C, then an aliquot was added to erythrocyte acetylcholinesterase (AChE) and the percentage of AChE inhibition was determined. The validity of the assay was confirmed by concomitant quantification of tabun by GC-MS. Different concentrations of cyclosarin were detoxified by CD-IBA in a concentration-dependent velocity. The ability to detoxify various nerve agents decreased in the order cyclosarin>sarin>tabun>>VX. Hereby, no detoxification of VX could be detected. Sarin was detoxified in a biphasic reaction with a fast reduction of inhibitory potential in the first phase and a slower detoxification in the second phase. CD-IBA detoxified tabun in a one phase decay and, compared to cyclosarin and sarin, a longer half-life was determined with tabun. The modified biological assay is appropriate for the initial semi-quantitative screening of candidate compounds for the detoxification of nerve agents. The beta-cyclodextrin derivative CD-IBA demonstrated its ability to detoxify different nerve agents.