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Journal of Mass Spectrometry : JMS Jun 2012The McLafferty rearrangement is an extensively studied fragmentation reaction for the odd-electron positive ions from a diverse range of functional groups and molecules....
Fragmentation of oxime and silyl oxime ether odd-electron positive ions by the McLafferty rearrangement: new insights on structural factors that promote α,β fragmentation.
The McLafferty rearrangement is an extensively studied fragmentation reaction for the odd-electron positive ions from a diverse range of functional groups and molecules. Here, we present experimental and theoretical results of 12 model compounds that were synthesized and investigated by GC-TOF MS and density functional theory calculations. These compounds consisted of three main groups: carbonyls, oximes and silyl oxime ethers. In all electron ionization mass spectra, the fragment ions that could be attributed to the occurrence of a McLafferty rearrangement were observed. For t-butyldimethylsilyl oxime ethers with oxygen in a β-position, the McLafferty rearrangement was accompanied by loss of the t-butyl radical. The various mass spectra showed that the McLafferty rearrangement is relatively enhanced compared with other primary fragmentation reactions by the following factors: oxime versus carbonyl, oxygen versus methylene at the β-position and ketone versus aldehyde. Calculations predict that the stepwise mechanism is favored over the concerted mechanism for all but one compound. For carbonyl compounds, C-C bond breaking was the rate-determining step. However, for both the oximes and t-butyldimethylsilyl oxime ethers with oxygen at the β-position, the hydrogen transfer step was rate limiting, whereas with a CH(2) group at the β-position, the C-C bond breaking was again rate determining. n-Propoxy-acetaldehyde, bearing an oxygen atom at the β-position, is the only case that was predicted to proceed through a concerted mechanism. The synthesized oximes exist as both the (E)- and (Z)-isomers, and these were separable by GC. In the mass spectra of the two isomers, fragment ions that were generated by the McLafferty rearrangement were observed. Finally, fragment ions corresponding to the McLafferty reverse charge rearrangement were observed for all compounds at varying relative ion intensities compared with the conventional McLafferty rearrangement.
Topics: Chemical Phenomena; Ethers; Gas Chromatography-Mass Spectrometry; Ions; Isomerism; Models, Chemical; Oximes; Silanes; Thermodynamics
PubMed: 22678949
DOI: 10.1002/jms.2986 -
Basic & Clinical Pharmacology &... Apr 2015The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in... (Comparative Study)
Comparative Study
The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.
Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Injections, Intramuscular; Lethal Dose 50; Male; Mice; Organophosphates; Oximes; Parasympatholytics; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime
PubMed: 25225130
DOI: 10.1111/bcpt.12327 -
Biomolecules Mar 2020Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates... (Review)
Review
Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.
Topics: Acetylcholinesterase; Cholinesterase Reactivators; GPI-Linked Proteins; Humans; Oximes; Patents as Topic
PubMed: 32178264
DOI: 10.3390/biom10030436 -
Medycyna Pracy Dec 2022Evidence of a change in the carcinogenicity category of butan-2-one oxime (MEKO) and the results of this change for manufacturing and using companies was presented and... (Review)
Review
Evidence of a change in the carcinogenicity category of butan-2-one oxime (MEKO) and the results of this change for manufacturing and using companies was presented and assessed. The online databases of scientific journals were reviewed, taking into account the reports on the harmonization of MEKO classification and labeling at EU level available on the ECHA website. Commission Regulation (EU) 2020/1182 introduced harmonized classification and labeling of MEKO for carcinogenicity to category 1B. The induction of tumors, the nature and importance of tumors for humans, and the sensitivity of the 2 species tested, both sexes - all of these factors support the classification of MEKO into the carcinogenicity category 1B. On the other hand, MEKO is negative in genotoxicity studies, including in mammalian cells and in animals. This is the argument that the classification of MEKO as carcinogen category 2 remains appropriate. The change in the MEKO carcinogenicity category results in legal consequences for companies, such as compliance with the conditions of REACH restriction, which includes restrictions on placing MEKO on the market for sale to the general public, keeping a register of works that require contact with MEKO or its mixtures containing MEKO in a concentration ≥0.1%. According to the opinion of MEKO suppliers, there is currently no practical MEKO substitute that has been so well researched, despite attempts to find it in recent years. The risk of additional liver cancer in the case of 40-year occupational exposure to MEKO is 4:100 000 at a concentration of approx. 0.7 mg/m, and it is an acceptable risk in accordance with the arrangements adopted in Poland. Compliance with the permissible concentrations of MEKO in the air of the working environment at this level should protect employees against the carcinogenic effect of MEKO. Med Pr. 2022;73(6):457-70.
Topics: Male; Animals; Female; Humans; Carcinogens; Butanones; Oximes; Butanes; Mammals
PubMed: 36537883
DOI: 10.13075/mp.5893.01311 -
Inorganic Chemistry Apr 2023A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a...
A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a significant drug payload (5.2 ± 0.9 oxime to MOF-808 molar ratio) and shows a sustained oxime release in simulated physiological media, leading to the successful reactivation of OP-inhibited acetylcholinesterase. At the same time, the hybrid system presents an efficient and moderately fast removal rate of a toxic organophosphorus model compound (diisopropylfluorophosphate) from simulated physiological media ( = 183 min; 95% removal rate after 24 h).
Topics: Humans; Oximes; Antidotes; Organophosphate Poisoning; Cholinesterase Reactivators; Metal-Organic Frameworks; Zirconium; Acetylcholinesterase; Cholinesterase Inhibitors; Organophosphorus Compounds
PubMed: 36939843
DOI: 10.1021/acs.inorgchem.3c00121 -
Molecules (Basel, Switzerland) Jun 2017Based on the structural framework of a pyriproxyfen metabolite, nineteen oxime ester derivatives were synthesized via reaction of the carboxylic acids with...
Based on the structural framework of a pyriproxyfen metabolite, nineteen oxime ester derivatives were synthesized via reaction of the carboxylic acids with 4-(2-(2-pyridinyloxy)ethoxy)benzaldehyde oxime. The corresponding structures were comprehensively characterized by ¹H-nuclear magnetic resonance (NMR), C-NMR, and electrospray ionization high-resolution mass spectrometry (ESI-HRMS). All of the compounds were screened for their insecticidal activities against and , and for their ovicidal activities against eggs. The results obtained show that most of the oxime ester derivatives displayed moderate to high insecticidal activities and ovicidal activities at a concentration of 600 ug/mL. In particular, the ovicidal activity of compounds , , , , and was determined to be 100%. Importantly, some of the compounds presented even higher biological activities than the reference compound pyriproxyfen. For example, compound displayed an insecticidal activity value of 87.5% against , whereas the activity value of pyriproxyfen was 68.3% at a concentration of 600 ug/mL. Among the synthesized compounds and exhibited broad biological activity spectra.
Topics: Animals; Aphids; Carboxylic Acids; Esters; Insecticides; Magnetic Resonance Spectroscopy; Molecular Structure; Moths; Oximes; Pyridines; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship
PubMed: 28594377
DOI: 10.3390/molecules22060958 -
Frontiers in Immunology 2022Vaccine adjuvants are key for optimal vaccine efficacy, increasing the immunogenicity of the antigen and potentiating the immune response. Saponin adjuvants such as the...
Vaccine adjuvants are key for optimal vaccine efficacy, increasing the immunogenicity of the antigen and potentiating the immune response. Saponin adjuvants such as the carbohydrate-based QS-21 natural product are among the most promising candidates in vaccine formulations, but suffer from inherent drawbacks that have hampered their use and approval as stand-alone adjuvants. Despite the recent development of synthetic derivatives with improved properties, their full potential has not yet been reached, allowing the prospect of discovering further optimized saponin variants with higher potency. Herein, we have designed, chemically synthesized, and immunologically evaluated novel oxime-derivatized saponin adjuvants with targeted structural modifications at key triterpene functionalities. The resulting analogues have revealed important findings into saponin structure-activity relationships, including adjuvant mechanistic insights, and have shown superior adjuvant activity in terms of significantly increased antibody response augmentation compared to our previous saponin leads. These newly identified saponin oximes emerge as highly promising synthetic adjuvants for further preclinical development towards potential next generation immunotherapeutics for future vaccine applications.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Adjuvants, Vaccine; Glycosides; Oximes; Saponins; Triterpenes; Vaccines
PubMed: 35603193
DOI: 10.3389/fimmu.2022.865507 -
Journal of the American Chemical Society Sep 2021Oxidative stress produces a variety of radicals in DNA, including pyrimidine nucleobase radicals. The nitrogen-centered DNA radical 2'-deoxycytidin-4-yl radical (dC·)...
Oxidative stress produces a variety of radicals in DNA, including pyrimidine nucleobase radicals. The nitrogen-centered DNA radical 2'-deoxycytidin-4-yl radical (dC·) plays a role in DNA damage mediated by one electron oxidants, such as HOCl and ionizing radiation. However, the reactivity of dC· is not well understood. To reduce this knowledge gap, we photochemically generated dC· from a nitrophenyl oxime nucleoside and within chemically synthesized oligonucleotides from the same precursor. dC· formation is confirmed by transient UV-absorption spectroscopy in laser flash photolysis (LFP) experiments. LFP and duplex DNA cleavage experiments indicate that dC· oxidizes dG. Transient formation of the dG radical cation (dG) is observed in LFP experiments. Oxidation of the opposing dG in DNA results in hole transfer when the opposing dG is part of a dGGG sequence. The sequence dependence is attributed to a competition between rapid proton transfer from dG to the opposing dC anion formed and hole transfer. Enhanced hole transfer when less acidic 6-methyl-2'-deoxyguanosine is opposite dC· supports this proposal. dC· produces tandem lesions in sequences containing thymidine at the 5'-position by abstracting a hydrogen atom from the thymine methyl group. The corresponding thymidine peroxyl radical completes tandem lesion formation by reacting with the 5'-adjacent nucleotide. As dC· is reduced to dC, its role in the process is traceless and is only detectable because of the ability to independently generate it from a stable precursor. These experiments reveal that dC· oxidizes neighboring nucleotides, resulting in deleterious tandem lesions and hole transfer in appropriate sequences.
Topics: DNA; DNA Damage; Deoxycytidine; Deoxyguanosine; Free Radicals; Oximes; Photolysis; Ultraviolet Rays
PubMed: 34467764
DOI: 10.1021/jacs.1c06425 -
Molecules (Basel, Switzerland) Jul 2019Nitric oxide (NO) is naturally synthesized in the human body and presents many beneficial biological effects; in particular on the cardiovascular system. Recently; many... (Review)
Review
Nitric oxide (NO) is naturally synthesized in the human body and presents many beneficial biological effects; in particular on the cardiovascular system. Recently; many researchers tried to develop external sources to increase the NO level in the body; for example by using amidoximes and oximes which can be oxidized in vivo and release NO. In this review; the classical methods and most recent advances for the synthesis of both amidoximes and oximes are presented first. The isomers of amidoximes and oximes and their stabilities will also be described; ()-amidoximes and ()-oximes being usually the most energetically favorable isomers. This manuscript details also the biomimetic and biological pathways involved in the oxidation of amidoximes and oximes. The key role played by cytochrome P450 or other dihydronicotinamide-adenine dinucleotide phosphate (NADPH)-dependent reductase pathways is demonstrated. Finally, amidoximes and oximes exhibit important effects on the relaxation of both aortic and tracheal rings alongside with other effects as the decrease of the arterial pressure and of the thrombi formation.
Topics: Isomerism; Nitric Oxide; Nitric Oxide Donors; Oxidation-Reduction; Oximes
PubMed: 31284390
DOI: 10.3390/molecules24132470 -
Chemico-biological Interactions Nov 2017Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little...
Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t of ∼1 h. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The C in the brain ranged between 0.03 and 0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.
Topics: Acetamides; Acetylcholinesterase; Animals; Blood-Brain Barrier; Cholinesterase Reactivators; Guinea Pigs; Kidney; Male; Oximes; Tissue Distribution
PubMed: 28941624
DOI: 10.1016/j.cbi.2017.09.016