Chemical Warfare Agents Soman Research Articles

Toxin-Blocking Textiles: Rapid, Benign, Roll-to-Roll Production of Robust MOF-Fabric Composites for Organophosphate Separation and Hydrolysis.

Current approaches to create zirconium-based metal-organic framework (MOF) fabric composites for catalysis, water purification, wound healing, gas sorption, and other applications often rely on toxic solvents, long reaction/post processing times, and batch methods hindering process scalability. Here, a novel mechanism was reported for rapid UiO-66-NH2 synthesis in common low-boiling-point solvents (water, ethanol, and acetic acid) and revealed acid-base chemistry promoting full linker dissolution and vapor-based crystallization. The mechanism enabled scalable roll-to-roll production of mechanically resilient UiO-66-NH2 fabrics with superior chemical protective capability. Solvent choice and segregated spray delivery of organic linker and metal salt MOF precursor solutions allowed for rapid MOF nucleation on the fiber surface and decreased the energy and time needed for post-processing, producing an activated composite in less than 165 min, far outpacing conventional MOF-fabric synthesis approaches. The MOF-fabric hydrolyzed and blocked permeation of the chemical warfare agent soman, outperforming the protection-standard activated carbon cloth. This work presents both chemical insights into Zr-MOF powder and fabric composite formation by a rapid, industrially relevant approach and demonstrates its practicality and affordability for high-performing personal protective equipment.

Stretchable and Multi-Metal-Organic Framework Fabrics Via High-Yield Rapid Sorption-Vapor Synthesis and Their Application in Chemical Warfare Agent Hydrolysis.

Protocols to create metal-organic framework (MOF)/polymer composites for separation, chemical capture, and catalytic applications currently rely on relatively slow solution-based processing to form single MOF composites. Here, we report a rapid, high-yield sorption-vapor method for direct simultaneous growth of single and multiple MOF materials onto untreated flexible and stretchable polymer fibers and films. The synthesis utilizes favorable reactant absorption into polymers coupled with rapid vapor-driven MOF crystallization to form high surface area (>250 m2/gcomposite) composites, including UiO-66-NH2, HKUST-1, and MOF-525 on spandex, nylon, and other fabrics. The resulting composites are robust and maintain their functionality even after stretching. Stretchable MOF fabrics enable rapid solid-state hydrolysis of the highly toxic chemical warfare agent soman and paraoxon-methyl simulant. We show that this approach can readily be scaled by solution spray-coating of MOF precursors and to large area substrates.

Bent‐But‐Not‐Broken: Reactive Metal‐Organic Framework Composites from Elastomeric Phase‐Inverted Polymers

AbstractA phase inversion process is used to fabricate composite beads from the metal–organic framework (MOF) UiO‐66‐NH2 and the elastomeric block copolymer poly(styrene‐block‐ethylene‐ran‐butylene‐block‐styrene) (SEBS) for improved performance over activated carbon‐based protective textiles. Textiles incorporating the best MOF‐composite materials reduced steady‐state permeation of the chemical warfare agent (CWAs) simulant, 2‐chloroethyl ethyl sulfide (CEES), by ≈60% versus activated carbon cloth. Additionally, the protection capabilities of the composite beads could be further tuned by adjusting bead size—textiles fabricated from smaller composite beads show enhanced diffusional properties whereas textiles generated from larger beads maximize protective capacity. The elastomeric beads also do not exhibit any attrition when subjected to a hardness test, whereas traditional pressing techniques result in materials with only a 20% retention of particle size. Furthermore, composites with increasing MOF content result in enhanced chemical capacity and reactivity, with the best composite outperforming activated carbon cloth against the CWAs soman (91% versus 17% reacted, respectively) and mustard (97% versus 0% reacted, respectively) over 24 h. The 80 wt% samples also have ≈1.4 and 2.2× higher adsorption capacity for soman and CEES, respectively, versus carbon cloth. Finally, mixing multiple MOFs results in optimal composites for the simultaneous filtration of chlorine and ammonia.

An Integrated Portable Multiplex Microchip Device for Fingerprinting Chemical Warfare Agents.

The rapid and reliable detection of chemical and biological agents in the field is important for many applications such as national security, environmental monitoring, infectious diseases screening, and so on. Current commercially available devices may suffer from low field deployability, specificity, and reproducibility, as well as a high false alarm rate. This paper reports the development of a portable lab-on-a-chip device that could address these issues. The device integrates a polymer multiplexed microchip system, a contactless conductivity detector, a data acquisition and signal processing system, and a graphic/user interface. The samples are pre-treated by an on-chip capillary electrophoresis system. The separated analytes are detected by conductivity-based microsensors. Extensive studies are carried out to achieve satisfactory reproducibility of the microchip system. Chemical warfare agents soman (GD), sarin (GB), O-ethyl S-[2-diisoproylaminoethyl] methylphsophonothioate (VX), and their degradation products have been tested on the device. It was demonstrated that the device can fingerprint the tested chemical warfare agents. In addition, the detection of ricin and metal ions in water samples was demonstrated. Such a device could be used for the rapid and sensitive on-site detection of both chemical and biological agents in the future.

Assessment of exogenous melatonin action on mouse liver cells after exposure to soman

Melatonin is a hormone with many different biological activities and therefore seems to be an important factor reducing the harmful effects caused by toxic organophosphorus compounds. In this study, we attempted to evaluate the protective effect of melatonin on liver cells of mice challenged with chemical warfare agent-soman. The study was conducted at the level of ultrastructural and biochemical changes (analysis of the activity of model lysosomal enzymes and assessment of the level of lipid peroxidation). Significant biochemical and ultrastructural changes were found in the studied mouse hepatocytes after administration of soman alone, and soman in combination with melatonin, and the scope of the disclosed changes was dependent on the time of action of the examined factors. Melatonin has shown protective action, shielding liver cells from toxic effects of soman, which may result from its antioxidant properties and stimulation of the lysosomal compartment, the system coordinating the isolation and removal of cell-threatening processes.

Experimental and computational study of the inclusion complexes of β-cyclodextrin with the chemical warfare agent soman (GD) and commonly used simulants

The inclusion complexation of the Chemical Warfare Agent soman (GD) by β-cyclodextrin is studied by both experimental and computational approaches.

Fate and degradation of the chemical warfare agent soman on sands

Soman is one of the most toxic nerve agents of the known chemical warfare agents. There is actually few knowledge on the behavior of soman in the event of an environmental contamination. It is in particular unknown whether soman remains on a given surface, evaporates into air, or degrades. Here, we studied the evaporation of soman deposited on silica sand using a laboratory-sized wind tunnel, thermal desorption, and gas chromatography. We also investigated the degradation of soman on silica sand by 31phosphorus solid state magic angle spinning nuclear magnetic resonance and gas chromatography–mass spectrometry. Results show that a drop of soman on silica sand spreads laterally while evaporating. The maximum vapor concentration was found when the spreading of the soman drop was maximum on the surface. Simultaneously, soman was absorbed gradually into the pore of sand and degraded to O-pinacolyl-methylphosphonic acid following a pseudo-first-order rate reaction over weeks. To our best knowledge, this is the first report on the fate of soman in a sandy environment.

Disruption of a binary organogel by the chemical warfare agent soman (GD) and common organophosphorus simulants

The chemical warfare agent (CWA) soman (GD) acts as a molecular stimulus for the disruption of an anthracene-based binary organogel prepared in cyclohexane.

Magnetically separable reactive sorbent based on the CeO2/γ-Fe2O3 composite and its utilization for rapid degradation of the organophosphate pesticide parathion methyl and certain nerve agents

A new kind of magnetically separable composite consisting of maghemite grains and cerium oxide nanocrystalline surface layer (CeO2/γ-Fe2O3) was successfully used as so called “reactive sorbent” to decompose certain dangerous organophosphate compounds, including the organophosphorus pesticide parathion methyl and the chemical warfare agents soman and VX. The phosphatase-mimetic behaviour of the sorbent was also demonstrated. A reversed-mode co-precipitation of Fe3+/Fe2+ salts with aqueous ammonia was used to prepare the magnetite core, with the subsequent precipitation of cerous carbonate on the surfaces of the magnetite grains (again in the reversed mode) and its conversion to cerium oxide by calcination in the presence of air. The magnetite was converted to maghemite during calcination. Scanning electron microscopy (SEM), high-resolution transmission microscopy (HRTEM) and electron diffraction (ED) confirmed the presence of the nanocrystalline layer of CeO2 on the sorbent surface. The CeO2/γ-Fe2O3 composite materials prepared at the optimum temperatures of 300–400°C exhibited the highest degradation efficiency and simultaneously retained good magnetic properties. Very high degradation rates (reaction half-lives of approximately ten minutes or less) were achieved at ambient temperature, with the degree of conversion approaching 100%. The facile separability of the sorbents using, for example, permanent magnets may enable their versatile use in various decontamination strategies.

Hydrogen bond-mediated recognition of the chemical warfare agent soman (GD)

NMR titration studies in acetonitrile-d(3)/DMSO-d(6) mixtures demonstrate that diindolylurea-based receptors can form complexes with the organophosphorus nerve agent soman in organic solution.

Synergism of Activated Carbon and Undoped and Nitrogen‐doped TiO2 in the Photocatalytic Degradation of the Chemical Warfare Agents Soman, VX, and Yperite

Efficient photocatalytic decomposition of chemical warfare agents is a process that may find application in emergency situations or for the controlled destruction of chemical warfare stockpiles. A series of heterogeneous photocatalysts comprising TiO2-activated carbon or N-TiO2-activated carbon composites exhibit excellent photocatalytic activity to effect the complete decomposition of yperite, soman, and VX in high concentrations. The remarkable photocatalytic activity arises from the synergism between adsorption on active carbon and photoactivity by titania. Nitridation makes the composite also active under visible-light irradiation.

Validation and Application of a GC-MS Method for Determining Soman Concentration in Rat Plasma Following Low-Level Vapor Exposure

A method for determining the chemical warfare agent soman (GD) in rat plasma has been validated and applied to low-level inhalation exposure studies currently being conducted. This method utilizes a fluoride ion-based regeneration assay with isotope dilution followed by large volume injection gas chromatography with ammonia chemical ionization mass spectrometric detection. Following sample preparation by solid phase extraction, chromatographic separation was achieved using a 14% cyanopropylphenyl/86% dimethyl polysiloxane capillary column with a total run time of 18.16 min. Soman and the deuterated isotope ((2)H(4)-soman) internal standard were detected using the selected ion monitoring mode and quantitated using the ammonia adduction ratio of m/z ions 200/204. A reproducible linear relationship was obtained for the quantitative concentration range of 10 pg on-column to 1000 pg on-column (r(2) = 0.9995) for standards in ethyl acetate with a detection limit of 5.65 pg on-column, and an average recovery of 93% in plasma. This sensitive method was successfully applied to the analysis of soman in rat plasma immediately post-exposure, resulting in the construction of dose-response plots.

Crystal structures of human carboxylesterase 1 in covalent complexes with the chemical warfare agents soman and tabun.

The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 A resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10(4)-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.

Direct detection of stereospecific soman hydrolysis by wild‐type human serum paraoxonase

Human serum paraoxonase 1 (HuPON1; EC 3.1.8.1) is a calcium-dependent six-fold beta-propeller enzyme that has been shown to hydrolyze an array of substrates, including organophosphorus (OP) chemical warfare nerve agents. Although recent efforts utilizing site-directed mutagenesis have demonstrated specific residues (such as Phe222 and His115) to be important in determining the specificity of OP substrate binding and hydrolysis, little effort has focused on the substrate stereospecificity of the enzyme; different stereoisomers of OPs can differ in their toxicity by several orders of magnitude. For example, the C+/-P- isomers of the chemical warfare agent soman (GD) are known to be more toxic by three orders of magnitude. In this study, the catalytic activity of HuPON1 towards each of the four chiral isomers of GD was measured simultaneously via chiral GC/MS. The catalytic efficiency (k(cat)/K(m)) of the wild-type enzyme for the various stereoisomers was determined by a simultaneous solution of hydrolysis kinetics for each isomer. Derived k(cat)/K(m) values ranged from 625 to 4130 mm(-1).min(-1), with isomers being hydrolyzed in the order of preference C+P+ > C-P+ > C+P- > C-P-. The results indicate that HuPON1 hydrolysis of GD is stereoselective; substrate stereospecificity should be considered in future efforts to enhance the OPase activity of this and other candidate bioscavenger enzymes.

Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells

Bioscavenger prophylactic therapy using purified human acetylcholinesterase (AChE) or butylcholinesterase (BChE) is a promising treatment for future protection against chemical warfare nerve agent exposure. Potential immune response due to the complex structure of cholinesterases, mutations, post-translational modifications, and genetic variation is a limiting factor against purified enzyme therapy. We investigated an alternative bioscavenger approach using forskolin, an inducer of intracellular cyclic AMP (cAMP), which activates AChE promoter and up-regulates its expression. A mouse neuronal cell line, Neuro 2A, was treated with various doses of forskolin and analysis of the expressed enzyme indicates that the AChE activity was significantly increased in cells exposed to repeated administration of the drug every other day for 7-10 days. Cholinesterase enzyme assays showed that the enzyme activity was increased approximately 2-fold for the extracellular enzyme and 3-fold for the intracellular enzyme. The optimal dose found for extracellular enzyme production was 12-24 microM forskolin, while the optimal dose for intracellular was 12 microM. In parallel with the rise in the AChE level, the morphology of forskolin-treated cells showed neurite growth with increasing doses. Forskolin treatment protects Neuro 2A cells from diisopropylflurophophate (DFP), a surrogate of the organophosphate chemical warfare agents soman and sarin, induced toxicity in Neuro 2A cells. These results indicate that transcriptional inducers, such as forskolin, can sufficiently up-regulate cellular AChE production and protect cells against organophosphate toxicity.

Histone acetylase inhibitor trichostatin A induces acetylcholinesterase expression and protects against organophosphate exposure

The biological effects of organophosphorous (OP) chemical warfare nerve agents (CWNAs) are exerted by inhibition of acetylcholinesterase (AChE), which prevents the hydrolysis of the neurotransmitter acetylcholine, leading to hypercholinergy, seizures/status epilepticus, respiratory/cardiovascular failure, and potentially death. Current investigations show that bioscavenger therapy using purified fetal bovine AChE in rodents and non-human primates and the more recently tested human butyrylcholinesterase, is a promising treatment for protection against multiple LD(50) CWNA exposures. Potential impediments, due to the complex structure of the enzyme, purification effort, resources, and cost have necessitated alternative approaches. Therefore, we investigated the effects of transcriptional inducers to enhance the expression of AChE to achieve sufficient protection against OP poisoning. Trichostatin A (TSA), an inhibitor of histone deacetylase that de-condenses the chromatin, thereby increasing the binding of transcription factors and mRNA synthesis, was evaluated for induction of AChE expression in various neuronal cell lines. Dose-response curves showed that a concentration of 333 nM TSA was optimal in inducing AChE expression. In Neuro-2A cells, TSA at 333 nM increased the extracellular AChE activity approximately 3-4 fold and intracellular enzyme activity 10-fold. Correlating with the AChE induction, TSA pre-treatment significantly protected the cells against exposure to the organophosphate diisopropylfluorophosphate, a surrogate for the chemical warfare agents soman and sarin. These studies indicate that transcriptional inducers such as TSA up-regulate AChE, which then can bioscavenge any organophosphates present, thereby protecting the cells from OP-induced cytotoxicity. In conclusion, transcriptional inducers are prospective new methods to protect against CWNA exposure.

Adamantyl tenocyclidines - adjuvant therapy in poisoning with organophosphorus compounds and carbamates

The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl- D-aspartate and muscarinic receptors showed low acute toxicity, having LD50 values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD50 of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD50 of aldicarb to >16.00 LD50 for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD50 of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.

Modification of near active site residues in organophosphorus hydrolase reduces metal stoichiometry and alters substrate specificity.

Organophosphorus hydrolase (OPH, EC 8.1.3.1) is a dimeric, bacterial enzyme that detoxifies many organophosphorus neurotoxins by hydrolyzing a variety of phosphonate bonds. The histidinyl residues at amino acid positions 254 and 257 are located near the bimetallic active site present in each monomer. It has been proposed that these residues influence catalysis by interacting with active site residues and the substrate in the binding pocket. We replaced the histidine at position 254 with arginine (H254R) and the one at position 257 with leucine (H257L) independently to form the single-site-modified enzymes. The double modification was also constructed to incorporate both changes (H254R/H257L). Although native OPH has two metals at each active site (four per dimer), all three of these altered enzymes possessed only two metals per dimer while retaining considerable enzymatic activity for the preferred phosphotriester (P-O bond) substrate, paraoxon (5-100% kcat). The three altered enzymes achieved a 2-30-fold increase in substrate specificity (kcat/Km) for demeton S (P-S bond), an analogue for the chemical warfare agent VX. In contrast, the substrate specificity for diisopropyl fluorophosphonate (P-F bond) was substantially decreased for each of these enzymes. In addition, H257L and H254R/H257L showed an 11- and 18-fold increase, respectively, in specificity for NPPMP, the analogue for the chemical warfare agent soman. These results demonstrate the ability to significantly enhance the specificity of OPH for various substrates by site-specific modifications, and it is suggested that changes in metal requirements may affect these improved catalytic characteristics by enhancing structural flexibility and improving access of larger substrates to the active site, while simultaneously decreasing the catalytic efficiency for smaller substrates.

ChemInform Abstract: Hydrolysis of Toxic Organophosphorus Compounds by o‐Iodosobenzoic Acid and Its Derivatives.

AbstractThe chemical warfare agents soman (Ia), sarin (Ib), tabun (Ic), and paraoxon (Ie) are hydrolyzed effectively in aqueous micellar (cat.2) solutions in the presence of the deprotonated form of iodosobenzoic acids (II) (cat.1) (e.g.