Lafont O

References (7)

Title : Functionalized cyclodextrins bearing an alpha nucleophile - A promising way to degrade nerve agents - Estour_2013_Chem.Biol.Interact_203_202
Author(s) : Estour F , Letort S , Muller S , Kalakuntla RK , Le Provost R , Wille T , Reiter G , Worek F , Lafont O , Gouhier G
Ref : Chemico-Biological Interactions , 203 :202 , 2013
Abstract : 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 alpha-nucleophile residue on the secondary face of beta-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.
ESTHER : Estour_2013_Chem.Biol.Interact_203_202
PubMedSearch : Estour_2013_Chem.Biol.Interact_203_202
PubMedID: 23123247

Title : New modified beta-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (I). Synthesis and preliminary screening: Evaluation of the detoxification using a half-quantitative enzymatic assay - Kalakuntla_2013_Toxicol.Lett_216_200
Author(s) : Kalakuntla RK , Wille T , Le Provost R , Letort S , Reiter G , Muller S , Thiermann H , Worek F , Gouhier G , Lafont O , Estour F
Ref : Toxicol Lett , 216 :200 , 2013
Abstract : Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on beta-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 beta-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 alpha-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.
ESTHER : Kalakuntla_2013_Toxicol.Lett_216_200
PubMedSearch : Kalakuntla_2013_Toxicol.Lett_216_200
PubMedID: 23201439

Title : Optimized strategies to synthesize beta-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers - Le Provost_2011_Org.Biomol.Chem_9_3026
Author(s) : Le Provost R , Wille T , Louise L , Masurier N , Muller S , Reiter G , Renard PY , Lafont O , Worek F , Estour F
Ref : Org Biomol Chem , 9 :3026 , 2011
Abstract : A new generation of organophosphate (OP) scavengers was obtained by synthesis of beta-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of beta-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8-10 were obtained from 5-7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8-12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.
ESTHER : Le Provost_2011_Org.Biomol.Chem_9_3026
PubMedSearch : Le Provost_2011_Org.Biomol.Chem_9_3026
PubMedID: 21373706

Title : In vitro detoxification of cyclosarin (GF) by modified cyclodextrins - Muller_2011_Toxicol.Lett_200_53
Author(s) : Muller S , Koller M , Le Provost R , Lafont O , Estour F , Wille T , Thiermann H , Worek F , Reiter G
Ref : Toxicol Lett , 200 :53 , 2011
Abstract : Developing potent detoxification strategies for prophylaxis and therapy against organophosphate (OP) intoxication still represents a challenging task. Clinical application of numerous investigated substances including enzymes and low molecular scavengers like metal ions or nucleophiles could not yet be realised due to profound disadvantages. Presenting a promising attempt, cyclodextrins (CDs) efficiently enhance the degradation of some organophosphorus compounds. The present study examined the in vitro GF degradation mediated by three CDs and a nucleophilic precursor performed by mass spectrometric detection with ammonia chemical ionisation. All four compounds caused a notable enhancement of GF detoxification that was synergistically accelerated in the case of 2-O-(3-carboxy-4-iodosobenzyl)-beta-cyclodextrin (IBA-beta-CD) with the alpha-nucleophile 2-iodosobenzoic acid (IBA) grafted on the secondary face of beta-cyclodextrin (beta-CD). In vitro toxicokinetic investigations of CD derivatives are needed to evaluate the effect of slow terminal elimination phase of the more toxic (-)-GF shown for two CD-derivatives underlining the necessity of detecting the complete kinetic course of inactivation. The observed effect of fast high affinity binding (20-30%) represents an additional therapeutic option of an extremely rapid reduction of GF concentration in vivo. Distinctive differences in the course of reaction are detected depending on beta-CD-derivatives, allowing a first inference of possible mechanisms and relevance of attached substituents. However, further profound investigation needs to be done to evaluate the basis of a clinical application of substituted CDs as potential detoxification agents.
ESTHER : Muller_2011_Toxicol.Lett_200_53
PubMedSearch : Muller_2011_Toxicol.Lett_200_53
PubMedID: 21035528

Title : Detoxification of nerve agents by a substituted beta-cyclodextrin: application of a modified biological assay - Wille_2009_Toxicology_265_96
Author(s) : Wille T , Tenberken O , Reiter G , Muller S , Le Provost R , Lafont O , Estour F , Thiermann H , Worek F
Ref : Toxicology , 265 :96 , 2009
Abstract : 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.
ESTHER : Wille_2009_Toxicology_265_96
PubMedSearch : Wille_2009_Toxicology_265_96
PubMedID: 19800384

Title : Improved access to 2-O-monobenzyl ethers of beta-cyclodextrin as precursors of catalysts for organophosphoryl esters hydrolysis - Masurier_2006_Carbohydr.Res_341_935
Author(s) : Masurier N , Estour F , Lefevre B , Brasme B , Masson P , Lafont O
Ref : Carbohydr Res , 341 :935 , 2006
Abstract : A comparative study of reaction conditions was performed for the synthesis of a 2-O-monobenzyl ether of cyclomaltoheptaose (beta-CD). Optimal conditions involved sodium ethoxide in Me(2)SO and benzyl bromide. The methodology was extended to the preparation of various 2(I)-O-iodobenzyl and 2(I)-O-carboxymethylbenzyl derivatives of beta-CD including a 3-carboxymethyl-4-iodobenzyl derivative of interest as precursor of an enzyme mimic to degrade the organophosphoryl ester diethyl 4-nitrophenyl phosphate (paraoxon).
ESTHER : Masurier_2006_Carbohydr.Res_341_935
PubMedSearch : Masurier_2006_Carbohydr.Res_341_935
PubMedID: 16530173

Title : Synthesis of 2-substituted beta-cyclodextrin derivatives with a hydrolytic activity against the organophosphorylester paraoxon - Masurier_2005_Eur.J.Med.Chem_40_615
Author(s) : Masurier N , Estour F , Froment MT , Lefevre B , Debouzy JC , Brasme B , Masson P , Lafont O
Ref : Eur Journal of Medicinal Chemistry , 40 :615 , 2005
Abstract : Beta-cyclodextrin was substituted by an iodosobenzoic acid derivative to create a catalytic hydrolytic activity against neurotoxic organophosphorus agents. The catalytic moiety was introduced on a secondary hydroxy group at the position 2 of a glucose unit. Several beta-cyclodextrin derivatives were obtained. In these derivatives, the methylene linker occupied all potential positions on the aromatic ring. Kinetic assays were carried out with paraoxon as organophosphate model. Three regioisomers hydrolyzed paraoxon, although the paraoxon-leaving group, para-nitrophenol, was not released from the beta-cyclodextrin torus.
ESTHER : Masurier_2005_Eur.J.Med.Chem_40_615
PubMedSearch : Masurier_2005_Eur.J.Med.Chem_40_615
PubMedID: 15935896