Mustards and Vesicants

Young, Robert A.; Bast, Cheryl B

doi:10.1016/b978-0-12-800159-2.00008-7

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…Nitrogen mustards (HN) are a type of blister agent classified as Schedule I CWA . These compounds, which are structurally and chemically related to the more notorious sulfur mustard (HD) used in World War I and other conflicts, can cause skin blistering along with ocular and respiratory damage . In addition, the early discovery of antitumor activity with nitrogen mustards led to the use of nitrogen mustard derivatives (such as chlorambucil and cyclophosphamide) as chemotherapeutic agents .…”

Section: Introductionmentioning

confidence: 99%

Covalent Adduction of Nitrogen Mustards to Model Protein Nucleophiles

Thompson

DeCaprio

2013

Chem. Res. Toxicol.

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Protein adducts have the potential to serve as unique biomarkers of exposure to compounds of interest. Many xenobiotics (or their metabolites) are electrophilic and therefore reactive with nucleophilic amino acid residues on proteins. Nitrogen mustards are reactive xenobiotics with potential use as chemical warfare agents (CWA) or agents of terrorist attack, in addition to being employed as chemotherapeutic agents. The present study utilized cysteine-, lysine-, and histidine-containing model peptides to characterize in vitro adduction of the nitrogen mustards mechloroethamine (HN-2) and tris-(2-chlorethyl)amine (HN-3) to these nucleophilic amino acid residues by means of liquid chromatography-tandem mass spectrometry. The study assessed the structure of adducts formed, the time course of adduct formation, concentration-response relationships, and temporal stability of adducts. Adduction was hypothesized to occur on all three model peptides via initial formation of a reactive aziridinium intermediate for both mechloroethamine and tris-(2-chlorethyl)amine, followed by covalent adduction to nucleophilic residues. While adduction was found to occur most readily with cysteine, it was also observed at lysine and histidine, demonstrating that adduction by mechloroethamine and tris-(2-chlorethyl)amine is possible at multiple nucleophilic sites. Following solid phase extraction cleanup, adducts formed with mechloroethamine were stable for up to three weeks. Adducts formed with tris-(2-chlorethyl)amine were less stable; however, hydrolyzed secondary adducts were observed throughout the three week period. This study demonstrates that the nitrogen mustards mechloroethamine and tris-(2-chlorethyl)amine form stable adducts with reactive protein nucleophiles other than cysteine.

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Section: Introductionmentioning

confidence: 99%

Covalent Adduction of Nitrogen Mustards to Model Protein Nucleophiles

Thompson

DeCaprio

2013

Chem. Res. Toxicol.

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“…The enzyme phosphotriesterase (PTE) is highly active in catalyzing the hydrolysis of phosphate ester bonds; , however, enzyme deactivation and relatively short enzyme shelf lives (at least at ambient temperature) place limits on the circumstances and range of conditions in which PTE may find practical use . As a result, bioinspired materials that mimic the active site in PTE have been explored for the destruction of nerve agents. − Zirconium metal–organic frameworks (MOFs) are some of the most promising candidates for catalytic nerve agent hydrolysis, as they have been found to be very effective for rapid hydrolysis of the phosphate ester bond. − As for the degradation of sulfur mustard, hydrolysis can be challenging due to its oily consistency and water immiscibility . Therefore, the hydrolysis of sulfur mustard (Scheme c) is usually slow and incomplete, owing to low water solubility and the formation of intermediate products that interfere with subsequent hydrolysis. , A more promising route for sulfur mustard detoxification is partial oxidation, in which sulfur mustard is oxidized to bis-2-chloroethyl sulfoxide (Scheme c). − It should be noted that full oxidation of sulfur mustard produces a sulfone that is itself toxic. , Thus, various oxidants and potential catalysts have been evaluated with the goal of achieving partial oxidation of sulfur mustard to the nontoxic sulfoxide product. ,− To this end, we recently demonstrated the use of singlet oxygen ( 1 O 2 ), generated by a porphyrinic MOF, for efficient and selective oxidation of sulfur mustard to the nontoxic sulfoxide product. , …”

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confidence: 99%

Dual-Function Metal–Organic Framework as a Versatile Catalyst for Detoxifying Chemical Warfare Agent Simulants

et al. 2015

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The nanocrystals of a porphyrin-based zirconium(IV) metal-organic framework (MOF) are used as a dual-function catalyst for the simultaneous detoxification of two chemical warfare agent simulants at room temperature. Simulants of nerve agent (such as GD, VX) and mustard gas, dimethyl 4-nitrophenyl phosphate and 2-chloroethyl ethyl sulfide, have been hydrolyzed and oxidized, respectively, to nontoxic products via a pair of pathways catalyzed by the same MOF. Phosphotriesterase-like activity of the Zr6-containing node combined with photoactivity of the porphyrin linker gives rise to a versatile MOF catalyst. In addition, bringing the MOF crystals down to the nanoregime leads to acceleration of the catalysis.

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“…Exposure to HD can directly affect lung morphology. When inhaled in sufficient amounts, HD induces apoptosis and/or necrosis of the respiratory tract epithelium resulting in the sloughing of this lining [6][7][8]. This process can lead to specific negative clinical outcomes, such as pulmonary obstruction and increased susceptibility to secondary infection [7].…”

Section: Inflammationmentioning

confidence: 99%

“…Since World War I, HD has been used in several different conflicts in both the 20th and 21st centuries, including the Japanese Occupation of China (1937China ( -1945 [3], the Iran-Iraq War (1980)(1981)(1982)(1983)(1984)(1985)(1986)(1987)(1988) [4], and most recently the occupation of Iraq by the terrorist group Islamic State of Iraq and the Levant (ISIL) (2014-2017) [5]. HD is currently considered a serious threat for use due to the large stockpiles still in existence and the relative ease of both acquiring the necessary materials and the production process [6,7].…”

Section: Introductionmentioning

confidence: 99%

Proteomic, Metabolomic, and Lipidomic Analyses of Lung Tissue Exposed to Mustard Gas

et al. 2022

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Sulfur mustard (HD) poses a serious threat due to its relatively simple production process. Exposure to HD in the short-term causes an inflammatory response, while long-term exposure results in DNA and RNA damage. Respiratory tract tissue models were exposed to relatively low concentrations of HD and collected at 3 and 24 h post exposure. Histology, cytokine ELISAs, and mass spectrometric-based analyses were performed. Histology and ELISA data confirmed previously seen lung damage and inflammatory markers from HD exposure. The multi-omic mass spectrometry data showed variation in proteins and metabolites associated with increased inflammation, as well as DNA and RNA damage. HD exposure causes DNA and RNA damage that results in variation of proteins and metabolites that are associated with transcription, translation and cellular energy.

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Mustards and Vesicants

Cited by 5 publications

References 54 publications

Covalent Adduction of Nitrogen Mustards to Model Protein Nucleophiles

Covalent Adduction of Nitrogen Mustards to Model Protein Nucleophiles

Dual-Function Metal–Organic Framework as a Versatile Catalyst for Detoxifying Chemical Warfare Agent Simulants

Proteomic, Metabolomic, and Lipidomic Analyses of Lung Tissue Exposed to Mustard Gas

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