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1.
Chem Biol Interact ; 326: 109111, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32413347

RESUMO

Human scalp hair is a biological matrix that can trap chemical vapours from explosives (TNT), drugs (THC) and chemical weapons (yperite). The external contamination of human's hair following exposure to organophosphorus (OP) nerve agent was simulated by model compounds: triethyl phosphate (TEP) and diisopropyl fluorophosphate (DFP). In this work were exposed strands of hair to vapours of TEP and DFP (3 and 7 ppmv) to model sorption kinetics. Sorption isotherms were also investigated at several contamination levels (80-3000 mg min.m-3). OP nerve agent simulants were extracted from hair by soaking in DCM. Raw extracts were analysed in GC-MS/MS to quantify each simulant content in hair. Results were fitted by applying isotherm or kinetic equations. The best model was found to be bimodal first-order, suggesting the co-existence of two different mechanisms of sorption. The best equation to describe OP vapours incorporation on hair was Freundlich model. Thus hair can be used as a passive sensor able to trap chemical G-agents and can also offer valuable information regarding both individual contamination and proof of exposure to chemical weapons.


Assuntos
Substâncias para a Guerra Química/química , Cabelo/química , Couro Cabeludo/química , Humanos , Isoflurofato/química , Gás de Mostarda/química , Agentes Neurotóxicos/química , Organofosfatos/química , Compostos Organofosforados/química
2.
Chem Biol Interact ; 326: 109139, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32454005

RESUMO

Since several decades oximes have been used as part of treatment of nerve agent intoxication with the aim to restore the biological function of the enzyme acetylcholinesterase after its covalent inhibition by organophosphorus compounds such as pesticides and nerve agents. Recent findings have illustrated that, besides oximes, certain Mannich phenols can reactivate the inhibited enzyme very effectively, and may therefore represent an attractive complementary class of reactivators. In this paper we further probe the effect of structural variation on the in vitro efficacy of Mannich phenol based reactivators. Thus, we present the synthesis of 14 compounds that are close variants of the previously reported 4-amino-2-(1-pyrrolidinylmethyl)-phenol, a very effective non-oxime reactivator, and 3 dimeric Mannich phenols. All compounds were assessed for their ability to reactivate human acetylcholinesterase inhibited by the nerve agents VX, tabun, sarin, cyclosarin and paraoxon in vitro. It was confirmed that the potency of the compounds is highly sensitive to small structural changes, leading to diminished reactivation potency in many cases. However, the presence of 4-substituted alkylamine substituents (as exemplified with the 4-benzylamine-variant) was tolerated. More surprisingly, the dimeric compounds demonstrated non-typical behavior and displayed some reactivation potency as well. Both findings may open up new avenues for designing more effective non-oxime reactivators.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/química , Agentes Neurotóxicos/farmacologia , Oximas/química , Oximas/farmacologia , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Reativadores da Colinesterase/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Relação Estrutura-Atividade
3.
Toxicol Lett ; 319: 237-241, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31738974

RESUMO

The RSDL® (Reactive Skin Decontamination Lotion) Kit contains a lotion-impregnated sponge extensively studied for the removal or neutralization of chemical warfare agents from skin. Pilot investigation of efficacy with industrial threat compounds noted that synthetic opioid fentanyl citrate was removed by the RSDL Kit but not chemically inactivated by the lotion. This implies that after use the RSDL Kit will contain intact fentanyl, which may pose a dermal health hazard if the fentanyl is then transferred to skin after use without proper handling. This in vitro investigation studied the contaminated RSDL Kit using three different concentrations of fentanyl with a skin contact time of 15 min under direct interaction from passive contact, light touch, and leaning with one hand. It was demonstrated that the expected transfer of fentanyl from contaminated RSDL depends on 1) the concentration of fentanyl and 2) the area of the exposed surface. From a toxicological perspective, the contact risk of fentanyl under the conditions tested can be considered low but not absent. The present study determined that a contaminated RSDL Kit, used for removal of fentanyl, should be handled with proper care. Use of protective gloves in operational use and washing skin afterwards is advised to prevent undesired contamination.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/análise , Contaminação de Medicamentos , Fentanila/efeitos adversos , Fentanila/análise , Creme para a Pele/efeitos adversos , Creme para a Pele/análise , Animais , Substâncias para a Guerra Química/química , Técnicas In Vitro , Projetos Piloto , Medição de Risco , Absorção Cutânea , Suínos
4.
Toxicol Lett ; 321: 1-11, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31846690

RESUMO

Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O-alkyl-N,N-dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O-ethyl-N,N- dimethyl phosphoramidocyanidate (GA), O-ethyl-N,N-ethyl(methyl) phosphoramidocyanidate, and O-ethyl-N,N-diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro, with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides-K525, K414, and K351-have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins.


Assuntos
Substâncias para a Guerra Química/metabolismo , Organofosfatos/metabolismo , Albumina Sérica Humana/metabolismo , Animais , Sítios de Ligação , Substâncias para a Guerra Química/química , Feminino , Hemoglobinas/metabolismo , Humanos , Ligação de Hidrogênio , Imunoglobulina G/metabolismo , Lisina , Masculino , Espectrometria de Massas , Simulação de Dinâmica Molecular , Organofosfatos/química , Ligação Proteica , Conformação Proteica , Coelhos , Albumina Sérica Humana/química , Relação Estrutura-Atividade
5.
Toxicology ; 430: 152346, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31857189

RESUMO

V-type agents are highly toxic organophosphorus nerve agents that inhibit acetylcholinesterase in the nervous system, causing a series of poison symptoms. Trace analytical methods are essential for the specific verification of exposure to these agents, especially for human exposure. This paper investigates the phosphonylated and disulfide adducts between human ceruloplasmin and O-ethyl S-(2-(diisopropylamino)ethyl) methylphosphonothioate (VX), O-isobutyl S-(2-(diethylamino)ethyl) methylphosphonothioate (VR), and O-butyl S-(2-(diethylamino)ethyl) methylphosphonothioate (Vs). After being digested by trypsin, the mixture of peptides was separated by a nano-liquid chromatography (nano-LC) and analyzed using quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS). The sensitive LC-MS/MS-assisted proteomics approach was developed to achieve the identification of human exposure to V-type agents based on these modified sites; results revealed that potential biomarkers could be derived from adducts based on the sulfur- and phosphorus-containing groups of V-type agents. This work offered a novel insight into the mechanism of disulfide-containing adducts resulting from the replacement of disulfide bridges by the thiolate groups from the V-type agents. Moreover, four disulfide adducts on human ceruloplasmin were also discovered during this research, specifically confirming exposure to the V-type agents. Furthermore, molecular simulation testified to the reactivity of the modified sites. Collectively, our findings suggest that the eleven binding sites on human ceruloplasmin have the potential use as a selective marker for prediction the V-type agent exposure in humans.


Assuntos
Ceruloplasmina/metabolismo , Substâncias para a Guerra Química/toxicidade , Etilaminas/toxicidade , Agentes Neurotóxicos/toxicidade , Substâncias para a Guerra Química/química , Cromatografia Líquida , Humanos , Simulação de Acoplamento Molecular , Agentes Neurotóxicos/química , Compostos Organotiofosforados/toxicidade , Proteômica , Espectrometria de Massas em Tandem
7.
Asian Pac J Cancer Prev ; 20(7): 2117-2123, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350974

RESUMO

Background: Ricin has been reported as a potential chemical for cancer treatment. However, so far, the application of ricin in cancer treatment is very limited because of its non-specificity. Methods: In this study, ricin were conjugated/ encapsulated with DOTAP/DOPE liposome to form ricin-liposome complexes (ricin-lipososme1, ricin-liposome2, ricin-liposome3 and ricin-liposome4). Characteristics of ricin-liposome complexes were analyzed and their effects on survival, apoptosis, migration, invasion and tumor formation of SKMEL-28 melanoma cells were examined by carrying out the MTT assay, apoptosis assay, scratch wound healing assay, invasion assay and soft-agar colony formation assay, respectively. Results: Ricin-liposome complexes had even size-distribution with average size of around 340 nm. These ricin-liposome complexes were able to penetrate into the cells via endocytosis with the highest ability of the ricinliposome3. It also showed that ricin-liposome3 expressed very high toxicity with the IC50 of 62.4 ng/mL and followed by ricin-liposome4 (286.4 mg/mL), ricin-liposome2 (417.5 ng/mL), and ricin-liposome1 (604.3 ng/mL) to SKMEL-28 cells at 36 hours post treatment. At the concentrations of IC10 (10.1 ng/mL), ricin-liposome3 strongly induced necrosis and apoptosis of SKMEL-28 cells up to 25.6% and 11.4%, respectively. Moreover, ricin-liposome3 expressed great anticancer properties by decreasing the migration, invasion and tumor formation abilities of SKMEL-28 cells of 7.5 folds, 4.3 folds and 5.9 folds, respectively, compared with those of control SKMEL-28 cells. Conclusion: The obtained results from our study suggest that although ricin is listed as one of the most poisonous substances in nature, it can be used in the complex forms with liposome to increase its specificity to apply in treatment of melanoma and other cancers.


Assuntos
Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Lipossomos/administração & dosagem , Melanoma/tratamento farmacológico , Ricina/farmacologia , Cicatrização/efeitos dos fármacos , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/farmacologia , Humanos , Lipossomos/química , Melanoma/patologia , Ricina/química , Células Tumorais Cultivadas
8.
Chemistry ; 25(51): 11892-11902, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31309626

RESUMO

Semiconductor metal oxides (SMO)-based gas-sensing materials suffer from insufficient detection of a specific target gas. Reliable selectivity, high sensitivity, and rapid response-recovery times under various working conditions are the main requirements for optimal gas sensors. Chemical warfare agents (CWA) such as sarin are fatal inhibitors of acetylcholinesterase in the nerve system. So, sensing materials with high sensitivity and selectivity toward CWA are urgently needed. Herein, micro-nano octahedral Co3 O4 functionalized with hexafluoroisopropanol (HFIP) were deposited on a layer of reduced graphene oxide (rGO) as a double-layer sensing materials. The Co3 O4 micro-nano octahedra were synthesized by direct growth from electrospun fiber templates calcined in ambient air. The double-layer rGO/Co3 O4 -HFIP sensing materials presented high selectivity toward DMMP (sarin agent simulant, dimethyl methyl phosphonate) versus rGO/Co3 O4 and Co3 O4 sensors after the exposure to various gases owing to hydrogen bonding between the DMMP molecules and Co3 O4 -HFIP. The rGO/Co3 O4 -HFIP sensors showed high stability with a response signal around 11.8 toward 0.5 ppm DMMP at 125 °C, and more than 75 % of the initial response was maintained under a saturated humid environment (85 % relative humidity). These results prove that these double-layer inorganic-organic composite sensing materials are excellent candidates to serve as optimal gas-sensing materials.


Assuntos
Substâncias para a Guerra Química/análise , Óxidos/química , Propanóis/química , Substâncias para a Guerra Química/química , Gases , Grafite , Compostos Orgânicos
9.
Chem Biol Interact ; 309: 108714, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31228470

RESUMO

Acetylcholinesterase (AChE) is an enzyme which terminates the cholinergic neurotransmission, by hydrolyzing acetylcholine at the nerve and nerve-muscle junctions. The reversible inhibition of AChE was suggested as the pre-treatment option of the intoxications caused by nerve agents. Based on our derived 3D-QSAR model for the reversible AChE inhibitors, we designed and synthesized three novel compounds 8-10, joining the tacrine and aroylacrylic acid phenylamide moieties, with a longer methylene chain to target two distinct, toplogically separated anionic areas on the AChE. The targeted compounds exerted low nanomolar to subnanomolar potency toward the E. eel and human AChE's as well as the human BChE and showed mixed inhibition type in kinetic studies. All compounds were able to slow down the irreversible inhibition of the human AChE by several nerve agents including tabun, soman and VX, with the estimated protective indices around 5, indicating a valuable level of protection. Putative noncovalent interactions of the selected ligand 10 with AChE active site gorge were finally explored by molecular dynamics simulation suggesting a formation of the salt bridge between the protonated linker amino group and the negatively charged Asp74 carboxylate side chain as a significant player for the successful molecular recognition in line with the design strategy. The designed compounds may represent a new class of promising leads for the development of more effective pre-treatment options.


Assuntos
Substâncias para a Guerra Química/química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Substâncias Protetoras/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Domínio Catalítico , Substâncias para a Guerra Química/metabolismo , Inibidores da Colinesterase/metabolismo , Colinesterases/química , Humanos , Cinética , Simulação de Dinâmica Molecular , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Substâncias Protetoras/metabolismo , Relação Quantitativa Estrutura-Atividade , Soman/química , Soman/metabolismo
10.
Chem Biol Interact ; 308: 80-88, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100274

RESUMO

The organophosphorus chemical warfare agents were initially synthesized in the 1930's and are some of the most toxic compounds ever discovered. The standard means of decontamination are either harsh chemical hydrolysis or high temperature incineration. Given the continued use of chemical warfare agents there are ongoing efforts to develop gentle environmentally friendly means of decontamination and medical counter measures to chemical warfare agent intoxication. Enzymatic decontamination offers the benefits of extreme specificity and mild conditions, allowing their use for both environmental and medical applications. The most promising enzyme for decontamination of the organophosphorus chemical warfare agents is the enzyme phosphotriesterase from Pseudomonas diminuta. However, the catalytic activity of the wild-type enzyme with the chemical warfare agents falls far below that seen with its best substrates, and its stereochemical preference is for the less toxic enantiomer of the chiral phosphorus center found in most chemical warfare agents. Rational design efforts have succeeded in the dramatic improvement of the stereochemical preference of PTE for the more toxic enantiomers. Directed evolution experiments, including site-saturation mutagenesis, targeted error-prone PCR, computational design, and quantitative library analysis, have systematically improved the catalytic activity against the chemical warfare nerve agents. These efforts have resulted in greater than 4-orders of magnitude improvement in catalytic activity and have led to the identification of variants that are highly effective at detoxifying both G-type and V-type nerve agents. The best of these variants have the ability to prevent intoxication when delivered as a post-exposure treatment for VX and as a pre-exposure treatment for G-agent intoxication with observed protective factors up to 60-fold. Combining the best variant, H257Y/L303T, with a PCB polymer coating has enabled the development of a long lasting circulating prophylactic treatment that is highly effective against sarin.


Assuntos
Proteínas de Bactérias/metabolismo , Substâncias para a Guerra Química/metabolismo , Evolução Molecular , Compostos Organotiofosforados/metabolismo , Hidrolases de Triester Fosfórico/metabolismo , Substâncias para a Guerra Química/química , Descontaminação/métodos , Inativação Metabólica , Compostos Organotiofosforados/química , Pseudomonas/enzimologia , Estereoisomerismo
11.
Chem Commun (Camb) ; 55(37): 5367-5370, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994655

RESUMO

A library of 26 mixed ligand UiO-66 analogs was synthesized, characterized, and screened for catalytic degradation of the chemical warfare agent (CWA) simulant dimethyl 4-nitrophenylphosphate (DMNP). The MOFs were screened and compared to physical mixtures of the same single component MOFs. Several of the MOFs display higher catalytic activity than the parent UiO-66 and other single ligand UiO-66 analogues.


Assuntos
Substâncias para a Guerra Química/química , Estruturas Metalorgânicas/análogos & derivados , Catálise , Ligantes , Estruturas Metalorgânicas/síntese química , Microscopia Eletrônica de Varredura , Nitrofenóis/química , Compostos Organofosforados/química , Tamanho da Partícula
12.
Chem Res Toxicol ; 32(6): 1123-1133, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-30964658

RESUMO

Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2), and sulfur mustard are potent vesicants that modify and disrupt cellular macromolecules including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia mutated- and Rad3-related (ATR) as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between the HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 µM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (Ser1981), Chk2 (Thr68), H2AX (Ser139), and p53 (Ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.


Assuntos
Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Substâncias para a Guerra Química/farmacologia , Dano ao DNA , Mecloretamina/farmacologia , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Substâncias para a Guerra Química/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mecloretamina/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Tempo , Células Tumorais Cultivadas
13.
Chemistry ; 25(39): 9217-9229, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-30924220

RESUMO

The effective detoxification of chemical warfare agents, specifically nerve agents, is a pressing issue in the modern world. Due to the high toxicity of these molecules, simulants are often used in experiments as substitutes for the agents. However, there is little reason to believe that the current simulants used in the literature are optimal predictors of nerve agent reactivity. Density functional theory calculations were performed on the alkaline hydrolysis of over 100 organophosphate molecules to identify improved simulants for the G-series nerve agents soman and sarin, based on low toxicity and similarity to nerve agent hydrolysis energetics and degradation mechanism. This screening highlighted 5 molecules that have nearly identical reaction barriers to the actual agents, while being far less toxic. Quantitative structure-activity relationship (QSAR) models were also derived to determine the most significant molecular descriptors for describing the hydrolysis free energy barriers of these reactions. The optimal QSAR model was subjected to a thorough statistical analysis and validation procedure to confirm its predictive capacity, showing excellent quantitative and ranking accuracy. It was further shown that the model trained on G-series agents can reliably predict energetics for other organophosphate classes as well, including VX. Through these computational insights, experimentalists may be aided in accurately and safely studying these reactions with less toxic simulants.


Assuntos
Agentes Neurotóxicos/química , Organofosfatos/química , Relação Quantitativa Estrutura-Atividade , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/metabolismo , Teoria da Densidade Funcional , Hidrólise , Cinética , Agentes Neurotóxicos/metabolismo , Organofosfatos/metabolismo
14.
Biochemistry ; 58(15): 2039-2053, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30893549

RESUMO

The bacterial enzyme phosphotriesterase (PTE) is noted for its ability to hydrolyze many organophosphate compounds, including insecticides and chemical warfare agents. PTE has been the subject of multiple enzyme evolution attempts, which have been highly successful against specific insecticides and the G-type nerve agents. Similar attempts targeting the V-type nerve agents have failed to achieve the same degree of success. Enzyme evolution is an inherently complex problem, which is complicated by synergistic effects, the need to use analogues in high-throughput screening, and a lack of quantitative data to direct future efforts. Previous evolution experiments with PTE have assumed an absence of synergy and minimally screened large libraries, which provides no quantitative information about the effects of individual mutations. Here a systemic approach has been applied to a 28800-member six-site PTE library. The library is screened against multiple V-agent analogues, and a combination of sequence and quantitative activity analysis is used to extract data about the effects of individual mutations. We demonstrate that synergistic relationships dominate the evolutionary landscape of PTE and that analogue activity profiles can be used to identify variants with high activity for substrates. Using these approaches, multiple variants with kcat/ Km values for the hydrolysis of VX that were improved >1500-fold were identified, including one variant that is improved 9200-fold relative to wild-type PTE and is specific for the SP enantiomer of VX. Multiple variants that were highly active for ( SP)-VR were identified, the best of which has a kcat/ Km values that is improved 13400-fold relative to that of wild-type PTE.


Assuntos
Proteínas de Bactérias/química , Substâncias para a Guerra Química/química , Compostos Organofosforados/química , Compostos Organotiofosforados/química , Hidrolases de Triester Fosfórico/química , Adaptação Fisiológica/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Substâncias para a Guerra Química/metabolismo , Descontaminação , Evolução Molecular Direcionada , Hidrólise , Mutação , Organofosfatos/química , Organofosfatos/metabolismo , Compostos Organofosforados/metabolismo , Compostos Organotiofosforados/metabolismo , Hidrolases de Triester Fosfórico/genética , Hidrolases de Triester Fosfórico/metabolismo , Pseudomonas/enzimologia , Pseudomonas/genética , Estereoisomerismo , Especificidade por Substrato
15.
Int J Mol Sci ; 20(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862059

RESUMO

"Novichoks" is the name given to the controversial chemical weapons supposedly developed in the former Soviet Union between the 1970s and the 1990s. Designed to be undetectable and untreatable, these chemicals became the most toxic of the nerve agents, being very attractive for both terrorist and chemical warfare purposes. However, very little information is available in the literature, and the Russian government did not acknowledge their development. The intent of this review is to provide the IJMS readers with a general overview on what is known about novichoks today. We briefly tell the story of the secret development of these agents, and discuss their synthesis, toxicity, physical-chemical properties, and possible ways of treatment and neutralization. In addition, we also wish to call the attention of the scientific community to the great risks still represented by nerve agents worldwide, and the need to keep constant investments in the development of antidotes and ways to protect against such deadly compounds.


Assuntos
Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/toxicidade , Guerra Química , Agentes Neurotóxicos/química , Agentes Neurotóxicos/toxicidade , Organofosfatos/química , Organofosfatos/toxicidade , Animais , Fenômenos Químicos , Guerra Química/prevenção & controle , Substâncias para a Guerra Química/síntese química , Descontaminação , Humanos , Agentes Neurotóxicos/síntese química , Organofosfatos/síntese química
16.
Int J Mol Sci ; 20(5)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857127

RESUMO

Biological toxins are a heterogeneous group produced by living organisms. One dictionary defines them as "Chemicals produced by living organisms that have toxic properties for another organism". Toxins are very attractive to terrorists for use in acts of bioterrorism. The first reason is that many biological toxins can be obtained very easily. Simple bacterial culturing systems and extraction equipment dedicated to plant toxins are cheap and easily available, and can even be constructed at home. Many toxins affect the nervous systems of mammals by interfering with the transmission of nerve impulses, which gives them their high potential in bioterrorist attacks. Others are responsible for blockage of main cellular metabolism, causing cellular death. Moreover, most toxins act very quickly and are lethal in low doses (LD50 < 25 mg/kg), which are very often lower than chemical warfare agents. For these reasons we decided to prepare this review paper which main aim is to present the high potential of biological toxins as factors of bioterrorism describing the general characteristics, mechanisms of action and treatment of most potent biological toxins. In this paper we focused on six most danger toxins: botulinum toxin, staphylococcal enterotoxins, Clostridium perfringens toxins, ricin, abrin and T-2 toxin. We hope that this paper will help in understanding the problem of availability and potential of biological toxins.


Assuntos
Abrina/toxicidade , Toxinas Bacterianas/toxicidade , Bioterrorismo , Substâncias para a Guerra Química/toxicidade , Ricina/toxicidade , Toxina T-2/toxicidade , Abrina/química , Animais , Toxinas Bacterianas/química , Substâncias para a Guerra Química/química , Humanos , Dose Letal Mediana , Modelos Moleculares , Ricina/química , Toxina T-2/química
17.
Biosens Bioelectron ; 131: 119-127, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826646

RESUMO

Organophosphorus compounds (OPs) continue to represent a significant chemical threat to humans due to exposures from their use as weapons, their potential storage hazards, and from their continued use agriculturally. Existing methods for detection include ELISA and mass spectrometry. The new approach presented here provides an innovative first step toward a portable OP quantification method that surmounts conventional limitations involving sensitivity, selectivity, complexity, and portability. DNA affinity probes, or aptamers, represent an emerging technology that, when combined with a mix-and-read, free-solution assay (FSA) and a compensated interferometer (CI) can provide a novel alternative to existing OP nerve agent (OPNA) quantification methods. Here it is shown that FSA can be used to rapidly screen prospective aptamers in the biological matrix of interest, allowing the identification of a 'best-in-class' probe. It is also shown that combining aptamers with FSA-CI enables quantification of the OPNA metabolites, Sarin (NATO designation "G-series, B", or GB) and Venomous Agent X (VX) acids, rapidly with high selectivity at detection limits of sub-10 pg/mL in 25% serum (by volume in PBS). These results suggest there is potential to directly impact diagnostic specificity and sensitivity of emergency response testing methods by both simplifying sample preparation procedures and making a benchtop reader available for OPNA metabolite quantification.


Assuntos
Técnicas Biossensoriais , Substâncias para a Guerra Química/isolamento & purificação , Agentes Neurotóxicos/isolamento & purificação , Compostos Organotiofosforados/isolamento & purificação , Sarina/isolamento & purificação , Aminas/química , Substâncias para a Guerra Química/química , Cromatografia Líquida , Exposição Ambiental , Ensaio de Imunoadsorção Enzimática , Humanos , Limite de Detecção , Agentes Neurotóxicos/química , Compostos Organofosforados , Compostos Organotiofosforados/química , Sarina/sangue , Espectrometria de Massas em Tandem
18.
Molecules ; 24(5)2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30813539

RESUMO

Here, we introduced a novel thiourea-based rhodamine compound as a chromo-fluorogenic indicator of nerve agent Soman and its simulant diethyl chlorophosphate (DCP). The synthesized probe N-(rhodamine B)-lactam-2-(4-cyanophenyl) thiourea (RB-CT), which has a rhodamine core linked by a cyanophenyl thiosemicarbazide group, enabled a rapidly and highly sensitive response to DCP with clear fluorescence and color changes. The detection limit was as low as 2 × 10-6 M. The sensing mechanism showed that opening of the spirolactam ring following the phosphorylation of thiosemicarbazides group formed a seven-membered heterocycle adduct, according to MS analysis and TD-DFT calculations. RB-CT exhibited high detecting selectivity for DCP, among other organophosphorus compounds. Moreover, two test kits were employed and successfully used to detect real nerve agent Soman in liquid and gas phase.


Assuntos
Corantes Fluorescentes/síntese química , Compostos Organofosforados/análise , Rodaminas/química , Soman/análise , Tioureia/química , Substâncias para a Guerra Química/análise , Substâncias para a Guerra Química/química , Corantes Fluorescentes/química , Limite de Detecção , Estrutura Molecular , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/química , Compostos Organofosforados/química , Soman/química
19.
ACS Appl Mater Interfaces ; 11(8): 7927-7935, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30688436

RESUMO

Self-detoxifying materials capable of both capture and destruction of chemical warfare agents (CWAs) are highly desirable for efficient personal protection and safe handling of contaminated materials. Developing new strategies to improve CWA removal efficiency of these materials is highly relevant to CWA purification technology. Herein, we present novel photothermally enhanced catalytic detoxification of CWA simulants and its application in self-detoxifying gas filters. The material design features a well-defined core-shell nanostructure (CSN) consisting of an inner photothermal material and an outer microporous catalyst. As a demonstration, the CSN was obtained by growing a Zr-based metal-organic framework (MOF), UiO-66-NH2, onto bioinspired dopamine-melanin (Dpa) nanoparticles via heterogeneous nucleation induced by metal chelation. The resultant Dpa@UiO-66-NH2 CSN has increased the turnover frequency (TOF) of a nerve agent simulant, 4-nitrophenyl phosphate (DMNP), by 2.9- and 1.7-fold in the presence of NIR laser and simulated solar light, respectively. Further incorporation of Dpa@UiO-66-NH2 CSNs into polymer fibers by electrospinning has led to an even greater photothermal enhancement effect (5.8- and 3.2-fold TOF increase), achieving a faster DMNP degradation rate than the corresponding pure MOF powder for the first time and the shortest half-life of DMNP (1.8 min) among reported MOF-based self-detoxifying fabrics. The significant photothermal enhancement in the detoxification ability of Dpa@UiO-66-NH2 fabrics is attributed to the instantaneous heat transfer from the photothermal core to the catalytic shell and effective heat retention enabled by the surrounding polymer matrix. The Dpa@UiO-66-NH2 fabrics can be easily prepared on a large scale and demonstrate efficient protection against DMNP aerosols as stand-alone gas filters. This strategy of photothermally enhanced catalytic detoxification can be feasibly extended to other catalytic detoxification systems and holds promise for next-generation gas masks.


Assuntos
Substâncias para a Guerra Química/química , Melaninas/química , Estruturas Metalorgânicas/química , Catálise , Raios Infravermelhos , Luz , Nanopartículas/química , Porosidade , Temperatura , Zircônio/química
20.
Free Radic Biol Med ; 130: 1-7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352302

RESUMO

We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.


Assuntos
Substâncias para a Guerra Química/química , Cloranila/química , Agentes Neurotóxicos/química , Oximas/química , Compostos de Piridínio/química , Antídotos , Carcinógenos/química , Substâncias para a Guerra Química/toxicidade , Cloranila/toxicidade , Espectroscopia de Ressonância de Spin Eletrônica , Radicais Livres/química , Halogenação , Humanos , Modelos Teóricos , Agentes Neurotóxicos/toxicidade , Fenômenos de Química Orgânica , Oximas/toxicidade , Compostos de Pralidoxima/química , Compostos de Piridínio/toxicidade
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