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

Structure–efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds Sophie Letort1, Michaël Bosco1, Benedetta Cornelio1, Frédérique Brégier1, Sébastien Daulon2, Géraldine Gouhier1 and François Estour*1 Full Research Paper Address: 1Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France and 2DGA Maîtrise NRBC, Département Evaluation des effets des agents chimiques, 91710 Vert le Petit, France Email: François Estour* - Open Access Beilstein J. Org. Chem. 2017, 13, 417–427. doi:10.3762/bjoc.13.45 Received: 22 November 2016 Accepted: 10 February 2017 Published: 06 March 2017 This article is part of the Thematic Series "Superstructures with cyclodextrins: Chemistry and applications IV". * Corresponding author Guest Editor: G. Wenz Keywords: cyclodextrin; decontamination; enzyme mimic; nerve agents; organophosphorus pesticides © 2017 Letort et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract 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. Introduction Originally employed as pesticides, organophosphorus compounds were further developed as chemical warfare agents during the Second World War. These compounds act as potent irreversible inhibitors of cholinesterases [1-6] and are able to cause lethal intoxications [3]. Despite the measures adopted to reduce the risk of accidental poisoning by pesticides [7-11] and the Chemical Weapons Convention aiming at the non-proliferation of chemical weapons or their precursors, organophosphorus compounds still constitute a threat to civilian and military people. Moreover, due to the current geopolitical situation and the increasing number of terrorist attacks worldwide, more efficient means against nerve agents are required [12]. Four 417 Beilstein J. Org. Chem. 2017, 13, 417–427. steps have to be considered to reach this objective: detection, individual and collective protection, decontamination, and medical countermeasures. Because a contamination transfer can occur from victims or through contact with contaminated equipment, a rapid elimination of the toxic has to be envisaged. For this, a scavenging approach to trap and degrade the nerve agents seems especially promising and may consist in developing enzyme mimics able to hydrolyze the organophosphorus (OP) compounds under physiological conditions. In this context, cyclodextrins (CD) constitute attractive starting materials because, due to the inclusion properties of their internal cavity, they can form host–guest complexes in aqueous media by weak interactions with small hydrophobic molecules. In particular, these macromolecular structures display the interesting capability to include organophosphorus pesticides into their cavity [13-17]. However, their intrinsic ability to transform these compounds into low or non-toxic metabolites at physiological pH is weak [18-20]. Therefore, in order to display such metabolic efficiency under mild conditions, various monofunctionalization strategies of β-CD were studied [21,22]. The attachment of an α-nucleophilic functional group on β-CD is a promising strategy to degrade G agents such as soman, sarin, cyclosarin or tabun (Figure 1) [23-30]. In fact, these β-CD derivatives play a dual role in this process: the macrocycle traps the organophosphorus whilst the bound α nucleophile reacts with the toxic agent leading to a non-toxic derivative. Other scavengers bearing several α nucleophilic groups were described [31,32]. Recently, our team developed a synthesis of heterodifunctionalized β-CD derivatives bearing an iodosobenzoate group and an Figure 1: Structures of G agents. imidazole substituent [33]. We have proven that the presence of both substituents increased the detoxification rate of soman as compared to the monofunctionalized derivatives. However, the synergistic effect was regiodependent and only observed with the imidazole substituent located in position 2 of one methylated glucose unit and the α nucleophile in position 3 of the adjacent methylated glucose unit (compound 1, Figure 2). Herein we present an extended study focusing on the impact of covalently bound functional groups to macrocyclic β-cyclodextrin that are involved in the OP hydrolysis. Four new derivatives 2–5 were prepared (Figure 3) for this purpose. Compared to analog 1, scavenger 2 has a longer linker between the iodosobenzoate group and the methylated-β-cyclodextrin scaffold whilst scavenger 3 is characterized by a longer linker binding the imidazole ring to the CD derivative. Finally, compounds 4 and 5 are analogs of 2 bearing only one of these groups, either the α nucleophile or the imidazole ring, respectively. All five derivatives 1–5 were tested for their degradation ability against methyl paraoxon (Figure 4), selected as the pesticide model, and their efficiencies were compared. To demonstrate the importance of functionalizing the CDs and the influence of Figure 2: Scavenger based on a heterodifunctionalized β-cyclodextrin derivative. 418 Beilstein J. Org. Chem. 2017, 13, 417–427. Figure 3: Structures of β-cyclodextrin derivatives 2–5. the individual moieties, the experiments were performed using the modified scavengers (with the groups covalently attached to the macrocycle) and with mixtures of heptakis(2,3,6-trimethyl)β-cyclodextrin (TRIMEB) with 2-iodosobenzoic acid and/or imidazole, respectively. In addition, the degradation properties of the newly synthesized CD derivatives against methyl parathion and fenitrothion (Figure 4) were also investigated. Finally, compounds 1–4 were tested for their detoxification ability against the nerve agent soman. Results and Discussion Synthesis The regioselective disubstitution of diol 6 (Scheme 1) was the key step to access derivatives 2 and 3. The synthetic methodology consisted first in the selective introduction of the imidazole substituent in position 2 in unit B of 6 by making use of the higher acidity of this hydroxy group compared to the OH groups in positions 3 and 6. As expected, the Figure 4: Structures of pesticides tested. 419 Beilstein J. Org. Chem. 2017, 13, 417–427. Scheme 1: Synthetic pathway to derivatives 2 and 3 (Tr = trityl). substitution reaction w (...truncated)