Reaction of α-Peroxy Lactones with C, N, P, and S Nucleophiles:  Adduct Formation and Nucleophile Oxidation by Nucleophilic Attack at and Biphilic Insertion into the Peroxide Bond

1997 ◽  
Vol 62 (6) ◽  
pp. 1623-1629 ◽  
Author(s):  
Waldemar Adam ◽  
Lluís Blancafort
Keyword(s):  
Adduct Formation ◽  
Nucleophilic Attack ◽  
Peroxide Bond

scholarly journals Bromofatty aldehyde derived from bromine exposure and myeloperoxidase and eosinophil peroxidase modify GSH and protein

2018 ◽  
Vol 59 (4) ◽  
pp. 696-705 ◽  
Author(s):  
Mark A. Duerr ◽  
Elisa N. D. Palladino ◽  
Celine L. Hartman ◽  
James A. Lambert ◽  
Jacob D. Franke ◽  
...  
Keyword(s):  
Phorbol Myristate Acetate ◽  
Plasma Levels ◽  
Adduct Formation ◽  
Nucleophilic Attack ◽  
Fatty Aldehyde ◽  
Myristate Acetate ◽  
Protein Adduct ◽  
Protein Thiols ◽  
Hypobromous Acid ◽  
Activated Neutrophils

α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.

Kinetic and equilibrium studies of the σ-adduct forming reactions of 1,3,5-trinitrobenzene and picryl chloride with some carbon bases

1986 ◽  
Vol 64 (9) ◽  
pp. 1714-1720 ◽  
Author(s):  
Michael R. Crampton ◽  
Terence P. Kee ◽  
Jennifer R. Wilcock
Keyword(s):  
Adduct Formation ◽  
Nucleophilic Attack ◽  
Initial Reaction ◽  
Equilibrium Studies ◽  
Equilibrium Data ◽  
Picryl Chloride ◽  
Ring Position

Reaction of 1,3,5-trinitrobenzene (TNB) with the malononitrile anion in methanol yields a carbon-bonded σ-adduct, (3). Ionisation of the remaining exocyclic hydrogen is favourable and yields the dianion (4). The initial reaction of 1-chloro-2,4,6-trinitrobenzene similarly occurs at an unsubstituted ring position, but is followed by slower nucleophilic attack at the 1-position yielding the substituted product. A major difference in the reaction of the ethyl malononitrile anion with TNB is that the adduct formed (11) has no readily dissociable proton. Hence, here, conversion to the carbon-bonded adduct is less favourable. Kinetic and equilibrium data are reported for these reactions and are compared with data for adduct formation involving methoxide ions.

scholarly journals Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1560
Author(s):  
Laura Orian ◽  
Leopold Flohé
Keyword(s):  
Metabolic Regulation ◽  
Redox Regulation ◽  
Antioxidant Defense ◽  
Catalytic Efficiency ◽  
Antioxidant Defense System ◽  
Nucleophilic Attack ◽  
Glutathione Peroxidases ◽  
H2o2 Reduction ◽  
Thioredoxin Reductases ◽  
Peroxide Bond

Among the chalcogens, selenium is the key element for catalyzed H2O2 reduction. In organic synthesis, catalytic amounts of organo mono- and di-selenides are largely used in different classes of oxidations, in which H2O2 alone is poorly efficient. Biological hydroperoxide metabolism is dominated by peroxidases and thioredoxin reductases, which balance hydroperoxide challenge and contribute to redox regulation. When their selenocysteine is replaced by cysteine, the cellular antioxidant defense system is impaired. Finally, classes of organoselenides have been synthesized with the aim of mimicking the biological strategy of glutathione peroxidases, but their therapeutic application has so far been limited. Moreover, their therapeutic use may be doubted, because H2O2 is not only toxic but also serves as an important messenger. Therefore, over-optimization of H2O2 reduction may lead to unexpected disturbances of metabolic regulation. Common to all these systems is the nucleophilic attack of selenium to one oxygen of the peroxide bond promoting its disruption. In this contribution, we revisit selected examples from chemistry and biology, and, by using results from accurate quantum mechanical modelling, we provide an accurate unified picture of selenium’s capacity of reducing hydroperoxides. There is clear evidence that the selenoenzymes remain superior in terms of catalytic efficiency.

scholarly journals Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

2019 ◽  
Author(s):  
María A. Pajares ◽  
Tahl Zimmerman ◽  
Francisco J. Sánchez-Gómez ◽  
Adriana Ariza ◽  
María J. Torres ◽  
...  
Keyword(s):  
Residual Activity ◽  
Redox Status ◽  
Adduct Formation ◽  
Protein Adducts ◽  
Cellular Proteins ◽  
Nucleophilic Attack ◽  
Allergic Reactions ◽  
Lactam Antibiotic ◽  
Lower Capacity ◽  
Intracellular Redox Status

AbstractSerum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of amoxicillin-protein adducts formation. Consequently, we show that thiol-containing compounds, including dithiothreitol, N-acetyl-L-cysteine and glutathione, perform a nucleophilic attack on the amoxicillin molecule that is followed by an internal rearrangement leading to amoxicillin diketopiperazine, a known amoxicillin metabolite with residual activity. The effect of thiols is catalytic and can render complete amoxicillin conversion. Interestingly, this process is dependent on the presence of an amino group in the antibiotic lateral chain, as in amoxicillin and ampicillin. Furthermore, it does not occur for other β-lactam antibiotics, including cefaclor or benzylpenicillin. Biological consequences of thiol-mediated amoxicillin transformation are exemplified by a reduced bacteriostatic action and a lower capacity of thiol-treated amoxicillin to form protein adducts. Finally, modulation of the intracellular redox status through inhibition of glutathione synthesis influenced the extent of amoxicillin adduct formation with cellular proteins. These results open novel perspectives for the understanding of amoxicillin metabolism and actions, including the formation of adducts involved in allergic reactions.

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