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

Article abstract of DOI:10.3762/bjoc.13.45

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 substra

Full text of DOI:10.3762/bjoc.13.45

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
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 417–427.
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
doi:10.3762/bjoc.13.45
Received: 22 November 2016
Accepted: 10 February 2017
Published: 06 March 2017
Email:
François Estour* - francois.estour@univ-rouen.fr
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 cyclo-
dextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imida-
zole 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 com- the Chemical Weapons Convention aiming at the non-prolifera-
pounds were further developed as chemical warfare agents tion of chemical weapons or their precursors, organophos-
during the Second World War. These compounds act as potent phorus compounds still constitute a threat to civilian and mili-
irreversible inhibitors of cholinesterases [1-6] and are able to tary people. Moreover, due to the current geopolitical situation
cause lethal intoxications [3]. Despite the measures adopted to and the increasing number of terrorist attacks worldwide, more
reduce the risk of accidental poisoning by pesticides [7-11] and efficient means against nerve agents are required [12]. Four
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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 equip-
ment, 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 en-
zyme mimics able to hydrolyze the organophosphorus (OP)
compounds under physiological conditions.
Figure 1: Structures of G agents.
imidazole substituent [33]. We have proven that the presence of
In this context, cyclodextrins (CD) constitute attractive starting both substituents increased the detoxification rate of soman as
materials because, due to the inclusion properties of their compared to the monofunctionalized derivatives. However, the
internal cavity, they can form host–guest complexes in aqueous synergistic effect was regiodependent and only observed with
media by weak interactions with small hydrophobic molecules. the imidazole substituent located in position 2 of one methyl-
In particular, these macromolecular structures display the inter- ated glucose unit and the α nucleophile in position 3 of the adja-
esting capability to include organophosphorus pesticides into cent methylated glucose unit (compound 1, Figure 2).
their cavity [13-17]. However, their intrinsic ability to trans-
form these compounds into low or non-toxic metabolites at Herein we present an extended study focusing on the impact of
physiological pH is weak [18-20]. Therefore, in order to display covalently bound functional groups to macrocyclic β-cyclo-
such metabolic efficiency under mild conditions, various mono- dextrin that are involved in the OP hydrolysis. Four new deriva-
functionalization strategies of β-CD were studied [21,22]. The tives 2–5 were prepared (Figure 3) for this purpose. Compared
attachment of an α-nucleophilic functional group on β-CD is a to analog 1, scavenger 2 has a longer linker between the iodoso-
promising strategy to degrade G agents such as soman, sarin, benzoate group and the methylated-β-cyclodextrin scaffold
cyclosarin or tabun (Figure 1) [23-30]. In fact, these β-CD de- whilst scavenger 3 is characterized by a longer linker binding
rivatives play a dual role in this process: the macrocycle traps the imidazole ring to the CD derivative. Finally, compounds 4
the organophosphorus whilst the bound α nucleophile reacts and 5 are analogs of 2 bearing only one of these groups, either
with the toxic agent leading to a non-toxic derivative. Other the α nucleophile or the imidazole ring, respectively.
scavengers bearing several α nucleophilic groups were de-
scribed [31,32].
All five derivatives 1–5 were tested for their degradation ability
against methyl paraoxon (Figure 4), selected as the pesticide
Recently, our team developed a synthesis of heterodifunctional- model, and their efficiencies were compared. To demonstrate
ized β-CD derivatives bearing an iodosobenzoate group and an the importance of functionalizing the CDs and the influence of
Figure 2: Scavenger based on a heterodifunctionalized β-cyclodextrin derivative.
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Figure 3: Structures of β-cyclodextrin derivatives 2–5.
Results and Discussion
the individual moieties, the experiments were performed using
the modified scavengers (with the groups covalently attached to Synthesis
the macrocycle) and with mixtures of heptakis(2,3,6-trimethyl)- The regioselective disubstitution of diol 6 (Scheme 1) was the
β-cyclodextrin (TRIMEB) with 2-iodosobenzoic acid and/or key step to access derivatives 2 and 3.
imidazole, respectively. In addition, the degradation properties
of the newly synthesized CD derivatives against methyl The synthetic methodology consisted first in the selective intro-
parathion and fenitrothion (Figure 4) were also investigated. duction of the imidazole substituent in position 2 in unit B of 6
Finally, compounds 1–4 were tested for their detoxification by making use of the higher acidity of this hydroxy group com-
ability against the nerve agent soman.
pared to the OH groups in positions 3 and 6. As expected, the
Figure 4: Structures of pesticides tested.
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Scheme 1: Synthetic pathway to derivatives 2 and 3 (Tr = trityl).
substitution reaction with the benzyl-like reactant 7 led to a spectra showed chemical shifts attributable to the CH2 groups
higher yield than the reaction with the propyl analog 8 (50% linked to the imidazole and iodobenzoate moieties, similar to
versus 35%), but suffered from a slightly lower regioselectivity. those observed for the precursor of 1 [33]. The subsequent
In fact, 4% of the 3-monosubstituted regioisomer of 9 was also deprotection and oxidation–hydrolysis reactions of derivatives
formed, whereas less than 1% of the 3-monofunctionalized 13 and 14 afforded scavengers 2 and 3, respectively and were
regioisomer of 10 was observed for the reaction with electro- performed in one step using sodium periodate in acidic medium.
phile 8. Once the first group was introduced in position 2, the Compound 2 was obtained in good yield, but the steric
substitution reaction at O-3 on the adjacent unit A was per- hindrance of the benzylic group in derivative 14 decreased the
formed. Due to the lower reactivity of this alcohol group, an yield of scavenger 3.
excess of base and electrophile was required for this step. In ad-
dition, the presence of the sterically hindered trityl-protected The introduction of the methyl iodobenzoate substituent at O-3
imidazole reduced the accessibility of substrates 11 and 12 to was conducted starting from monohydroxy compound 15 [34].
position 3. Thus, compounds 13 and 14 were isolated in compa- After reaction with electrophile 12, compound 4 was obtained
rable yields of 37% and 27%, respectively and this time with- through oxidation and hydrolysis of intermediate 16 (Scheme 2)
out significantly different reactivities observed for the precur- using the same experimental conditions as applied for deriva-
sors 9 and 10.
tives 13 and 14. HSQC NMR analysis of 16 allowed the assign-
ment of the three CH2 groups of the propyl linker bearing the
High resolution mass spectrometry (ESI+ HRMS) analyses of benzene ring. Correlation signals were observed for the dia-
compounds 13 and 14 confirmed the presence of the two sub- stereotopic protons at 3.59 and 3.90 ppm with the 13C signal at
stituents bound to the macrocycle. Also the 1H and 13C NMR 73.1 ppm belonging to the carbon connected to the oxygen atom
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Scheme 2: Synthesis of compound 4.
at the C-3 position. In the same way, the HSQC spectrum high- ence of the organophosphorus compounds on the hydrolysis
lights a correlation between two other diastereotopic protons process.
2.50 and 2.75 ppm) and the benzylic carbon (31.9 ppm).
Finally, the quintuplet at 1.99 ppm correlated with the In a first step, 2-iodosobenzoic acid (IBA) was used as refer-
13C signal at 31.4 ppm was assigned to the third methylene ence compound to assess the efficiencies of derivatives 1, 2, and
group.
3 towards the hydrolysis of methyl paraoxon (Figure 5). All
scavengers 1–3 accelerated the transformation of the
The monosubstituted derivative 18 was prepared in good yield organophosphorus compound into p-nitrophenol compared to
by reaction of the tritylated imidazole 7 with monohydroxy IBA alone. Compound 2 was the most effective, while the
compound 17 in the presence of sodium hydride (Scheme 3) slowest pesticide hydrolysis was observed in the presence of de-
[35]. The 1H NMR signals of the diastereotopic methylene rivative 3. These results provided evidence that the relative po-
protons in product 18 were respectively observed at 4.57 and sition of the reactive group towards the phosphorus atom and
4.71 ppm, while the corresponding 13C signal connected to the the vicinity of the imidazole affect the efficiency of the scav-
aromatic group was detected at 67.0 ppm. After deprotection engers. In fact, the pesticide degradation was more effective for
under acidic conditions, the desired compound 5 was obtained the derivative possessing an n-propyl linker of the α-nucleo-
in 94% yield.
phile to the macrocycle (2 versus 1). On the other hand the
highest synergistic effect of the imidazole group was observed
for scavengers connected with this group through a methylene,
OPasic assays
A series of tests was undertaken with the aim to: i) estimate CH2 linker (1 versus 3).
whether the length and flexibility of the linker between the
imidazole and iodosobenzoate groups and the cyclodextrin At a higher concentration (0.5 mM) of scavengers 1, 2 or 3, we
affects the OPasic activity, ii) compare the results obtained with observed an improved efficiency for all three derivatives, com-
the scavengers with those obtained with a mixture of CD and pared to IBA (Figure 6) together with a reduced difference in
imidazole or iodosobenzoate, and iii) study the structural influ- their relative activities. For both studied concentrations
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Scheme 3: Synthesis of compound 5 (Tr = trityl).
Figure 5: Hydrolysis of methyl paraoxon (0.5 mM) in the presence of compounds 1, 2, 3 or 2-iodosobenzoic acid (IBA) at 0.25 mM concentration.
(0.25 and 0.5 mM), the catalysts 1–3 were poisoned by the scavenger 4, bearing only the α-nucleophile through a
formed p-nitrophenol after a determined time. This phenome- three-carbon atom linker showed a similar efficiency
non was already observed: the inclusion of the hydrolysis than 2. Therefore, it can be concluded for compound 2
product in the cyclodextrin cavity limits the catalyst regenera- that there is no synergistic effect between the imidazole
tion [27].
and the reactive groups. Thus, the imidazole substituent
is able to accelerate the degradation of methyl paraoxon,
Additional investigations were then performed with the mono- induced by the covalently attached α-nucleophile iodoso-
substituted cyclodextrin derivatives 4 and 5 (Figure 7). In the benzoate, only if IBA is bound close to the macrocycle
case of compound 5, no activity was observed. In contrast, (1 versus 3).
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Figure 6: Hydrolysis of methyl paraoxon (0.5 mM) in the presence of compounds 1, 2, 3 or 2-iodosobenzoic acid (IBA) at 0.5 mM concentration.
Figure 7: Hydrolysis of methyl paraoxon (0.5 mM) in the presence of compounds 2, 4, 5 or 2-iodosobenzoic acid (IBA) at 0.5 mM concentration.
In the presence of both, imidazole and compound 4 (Figure 8), mixture of IBA and compound 5 (Figure 8) led to a reduced
the rate of methyl paraoxon degradation was marginally in- hydrolysis efficiency of IBA. The same effect was observed for
creased with respect to scavenger 4 alone. On the other hand, a a mixture of IBA, imidazole and TRIMEB. Furthermore, adding
Figure 8: Hydrolysis of methyl paraoxon (0.5 mM) in the presence of mixtures of compounds 4, 5 with IBA or imidazole and in the presence of a mix-
ture of TRIMEB, 2-iodosobenzoic acid (IBA) and imidazole. The final concentrations of compounds 4, 5, 2-iodosobenzoic acid (IBA), imidazole and
TRIMEB were 0.5 mM.
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Beilstein J. Org. Chem. 2017, 13, 417–427.
one molar equivalent of IBA to TRIMEB even strengthened the Derivative 2 appeared as the most promising disubstituted
effect and it can be concluded that both, TRIMEB and com- cyclodextrin for the degradation of methyl paraoxon.
pound 5 at least partially inhibited the pesticide hydrolysis by Therefore, this compound was subsequently used in the hydro-
IBA. Therefore, when the α-nucleophile is not covalently bound lysis of other pesticides (Figure 9). Compound 2 was found to
to the macrocycle, the inclusion of paraoxon into the cyclo- hydrolyze the organophosphorus compounds in the following
dextrin cavity obviously protects the phosphate moiety of the order: fenitrothion < methyl parathion < methyl paraoxon while
pesticide from the external attack of the α-nucleophile. Clearly, IBA alone displayed a generally lower and similar efficiency
the covalent binding of the α-nucleophile to the β-cyclodextrin towards these three pesticides. This suggests that the electro-
scaffold leads to an increased hydrolytic activity.
philic character of the phosphorus atom plays a role in the
detoxification process (methyl parathion versus methyl
The relative abilities of IBA and compounds 1–4 (0.25 mM) to paraoxon). Moreover, the strength and depth of the pesticide
accelerate the methyl paraoxon (0.5 mM) hydrolysis were then inclusion into the cyclodextrin cavity undeniably influence the
measured by determining the pseudo-first-order rate constants degradation process. Indeed, it was shown that the lowest
during the initial course of the process (Table 1). Under the hydrolysis rates correspond to the highest dissociation con-
conditions, the cyclodextrin derivatives 1–4 are fully active stants from TRIMEB [36,37]. As methyl paraoxon represents
over the first 4 minutes. The absorbance increases linearly, thus the main and first metabolite of methyl parathion [38], scav-
indicating that no competitive inclusion of p-nitrophenol occurs enger 2 may be used in the late intervention after parathion
as a side reaction and the catalyst is prevented from poisoning. intoxication.
In the presence of the most active compound 2, 19.6% of
paraoxon were hydrolyzed after 4 minutes whereas a conver- The degradation of methyl parathion was also studied in pres-
sion of only 2.6% was observed using IBA alone. ence of compound 4. As already observed for methyl paraoxon
The comparison with the reaction conducted in the compound 4 promoted the hydrolysis of methyl parathion with
presence of IBA revealed that scavengers 1, 2, 3 and 4 comparable efficiency than 2 (Figure 10). This suggests that the
increased the catalytic factor by 5.5, 8.4, 2.9 and 8.2 times, re- introduction of an imidazole group on the scavenger having the
spectively.
iodosobenzoate bound through an n-propyl linker has no effect
Table 1: Estimated pseudo-first-order rate constant (k) and amount (%) of hydrolyzed methyl paraoxon over the first 4 minutes.a
IBA
1
2
3
4
k (10−3 min−1)
6.48
2.6
35.81
13.3
54.64
19.6
19.07
7.3
53.00
19.1
% of hydrolyzed methyl paraoxon
aConditions: 20 mM phosphate buffer, 13 mM CTAC, 2.9 vol % DMSO, 3 vol % CH3OH at 25 °C. The concentrations of 2-iodosobenzoic acid (IBA),
compounds 1, 2, 3 and 4 were 0.25 mM. The concentration of methyl paraoxon was 0.5 mM. The reactions were followed by UV–vis determination of
the released p-nitrophenol at 400 nm.
Figure 9: Influence of the pesticide structure on the hydrolytic efficiency of compound 2 (0.25 mM). Kinetic assays were carried out with methyl
paraoxon, methyl parathion or fenitrothion (0.5 mM).
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Beilstein J. Org. Chem. 2017, 13, 417–427.
Figure 10: Influence of TRIMEB, IBA and imidazole on the hydrolysis of methyl parathion (0.5 mM). The final concentrations of compounds 2, 4,
2-iodosobenzoic acid (IBA), imidazole and TRIMEB were 0.25 mM.
on the hydrolytic activity, irrespective of the nature of the pesti-
Table 2: Estimated pseudo-first-order rate constant (k) and
cide. Moreover, the hydrolysis rate of methyl parathion in the
presence of imidazole and derivative 4 did not change when
compared to scavenger 2. This result confirms the importance to
introduce the imidazole at a specific distance from the reactive
group. It is important to note that, contrary to methyl paraoxon,
in the case of methyl parathion, the use of an equimolar mix-
ture of IBA and TRIMEB didn’t affect the degradation of the
pesticide compared to IBA alone. The influence of the intermo-
lecular interactions between the pesticides and the methylated
oligosaccharide is of fundamental importance towards the deg-
radation process.
amount (%) of hydrolyzed methyl parathion over the first 4 minutes.a
IBA
1
4
k (10−3 min−1)
3.99
1.6
28.17 29.79
10.7 11.2
% of hydrolyzed methyl parathion
aConditions: 20 mM phosphate buffer, 13 mM CTAC, 2.9 vol % DMSO,
3 vol % CH3OH at 25 °C. The concentrations of 2-iodosobenzoic acid
(IBA), compounds 1 and 4 were 0.25 mM, respectively. The concentra-
tion of methyl parathion was 0.5 mM. The reactions were followed by
UV–vis determination of the released p-nitrophenol at 400 nm.
Finally, the scavengers 1–4 were tested for their ability to
prevent the inhibition of acetylcholinesterase by the chemical
warfare agent soman (Figure 11). The heterodifunctionalized
derivatives 1 and 3 were, this time, the most effective com-
pounds. Preincubation of compounds 1 and 3 with soman for
60 minutes reduced the inhibition of the enzyme by 70% and
60%, respectively, whilst 40% and 50% reduction was ob-
served with compounds 2 and 4 after the same pretreatment
The degradation efficiency of IBA and compounds 1 and 4
towards methyl parathion was also studied in terms of rate con-
stants (Table 2) within the initial 4 minutes. In the presence of
derivatives 1 and 4, 10–11% hydrolysis of the substrate were
observed and the catalytic factor increased by 7.1 and 7.5 times,
respectively, compared to free IBA.
Figure 11: Ability of compounds 1–4 in preventing the inhibition of acetylcholinesterase by soman (GD).
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Beilstein J. Org. Chem. 2017, 13, 417–427.
time. Moreover, scavengers 1 and 3 exhibited a detectable ac- Acknowledgements
tivity only after approximately 20 minutes incubation with Funding: DGA-MRIS and region Haute-Normandie are grate-
soman, whereas compounds 2 and 4 showed an even later effect fully acknowledged for PhD scholarship. The authors thank
reducing the inhibition by 30% after 50 minutes pretreatment. DGA Maîtrise NRBC (contract n°2014910080), DGA
Comparing the efficiencies of compounds 1 and 2 with those (« ASTRID maturation », ANR-14-ASMA-0003), ANR (ANR
obtained for methyl paraoxon, we observed a higher activity BLAN06-1_134538) and ANR-LABEX SynOrg for postdoc-
when the α-nucleophile is close to the macrocycle. Concerning toral fellowships (ANR-11-LABX-0029). Rouen University,
compounds 1 and 3, the vicinity of the imidazole substituent to INSA Rouen, CNRS, EFRD and Labex SynOrg (ANR-11-
the active group confirmed its benefit to accelerate the soman LABX-0029) are also acknowledged for their financial support.
degradation [33]. However, many parameters are involved in
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