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Emergency Medicine Clinics of North... Feb 2015Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of... (Review)
Review
Organophosphates (OPs) and carbamates have a wide variety of applications, most commonly as pesticides used to eradicate agricultural pests or control populations of disease-carrying vectors. Some OP and carbamates have therapeutic indications such as physostigmine. Certain organophosphorus compounds, known as nerve agents, have been employed in chemical warfare and terrorism incidents. Both classes inhibit acetylcholinesterase (AChE) enzymes, leading to excess acetylcholine accumulation at nerve terminals. In the setting of toxicity from either agent class, clinical syndromes result from excessive nicotinic and muscarinic neurostimulation. The toxic effects from OPs and carbamates differ with respect to reversibility, subacute, and chronic effects. Decontamination, meticulous supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management.
Topics: Antidotes; Carbamates; Disease Management; Environmental Exposure; Humans; Muscarinic Antagonists; Organophosphate Poisoning; Oximes; Poisoning
PubMed: 25455666
DOI: 10.1016/j.emc.2014.09.010 -
Nature Chemical Biology Jul 2016Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full...
Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.
Topics: Apoptosis; Dose-Response Relationship, Drug; Humans; Iron; Lipid Metabolism; Oximes; Structure-Activity Relationship; Sulfonamides
PubMed: 27159577
DOI: 10.1038/nchembio.2079 -
Methods in Molecular Biology (Clifton,... 2020Click chemistry has found wide application in bioconjugation, enabling control over the site of modification in biomolecules. Demonstrations of this chemistry to...
Click chemistry has found wide application in bioconjugation, enabling control over the site of modification in biomolecules. Demonstrations of this chemistry to construct chemically defined antibody-drug conjugates (ADCs) have increased in recent years, following studies that support benefits of homogeneity and site-specificity of drug placement on the antibody. In this chapter, a brief history of early applications of this chemistry in ADCs is presented. Examples of click chemistries that are utilized for ADC synthesis, including those currently undergoing clinical investigations, are enumerated. Protocols for two common conjugation methods based on carbonyl-aminooxy coupling and strain-promoted azide-alkyne cycloaddition are described.
Topics: Amino Acids; Antibodies, Monoclonal; Chemistry Techniques, Synthetic; Click Chemistry; Cycloaddition Reaction; Drug Development; Humans; Immunoconjugates; Oximes
PubMed: 31643051
DOI: 10.1007/978-1-4939-9929-3_6 -
Molecules (Basel, Switzerland) Jun 2023Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the... (Review)
Review
Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the structures of oxime ethers with specific biological activity have been collected and presented, and bactericidal, fungicidal, antidepressant, anticancer and herbicidal activities, among others, are described. The review includes both those substances that are currently used as drugs (e.g., fluvoxamine, mayzent, ridogrel, oxiconazole), as well as non-drug structures for which various biological activity studies have been conducted. To the best of our knowledge, this is the first review of the biological activity of compounds containing such a moiety. The authors hope that this review will inspire scientists to take a greater interest in this group of compounds, as it constitutes an interesting research area.
Topics: Ethers; Structure-Activity Relationship; Oximes; Fungicides, Industrial; Anti-Bacterial Agents; Anesthetics, General
PubMed: 37446703
DOI: 10.3390/molecules28135041 -
Chembiochem : a European Journal of... Sep 2022Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker...
Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker connecting the E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands, which therefore requires tedious optimization. The creation of "split PROTACs" from E3 Ubl and TP ligands modified with residues suitable for them to couple when simply mixed together would allow various combinations to be assessed in a combinatorial fashion, thus greatly easing the workload relative to a one-by-one synthesis of many different PROTACs (proteolysis targeting chimeras). We explore oxime chemistry here for this purpose. We show that PROTAC assembly occurs efficiently when the components are mixed at a high concentration, then added to cells. However, in situ coupling of the TP and E3 Ubl ligands is inefficient when these units are added to cells at lower concentrations.
Topics: Ligands; Oximes; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35802347
DOI: 10.1002/cbic.202200275 -
International Journal of Molecular... Nov 2023The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse... (Review)
Review
The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.
Topics: Ether; Oximes; Ethers; Structure-Activity Relationship; Ethyl Ethers
PubMed: 38069175
DOI: 10.3390/ijms242316854 -
Chemical Reviews Aug 2017The formation of oximes and hydrazones is employed in numerous scientific fields as a simple and versatile conjugation strategy. This imine-forming reaction is applied... (Review)
Review
The formation of oximes and hydrazones is employed in numerous scientific fields as a simple and versatile conjugation strategy. This imine-forming reaction is applied in fields as diverse as polymer chemistry, biomaterials and hydrogels, dynamic combinatorial chemistry, organic synthesis, and chemical biology. Here we outline chemical developments in this field, with special focus on the past ∼10 years of developments. Recent strategies for installing reactive carbonyl groups and α-nucleophiles into biomolecules are described. The basic chemical properties of reactants and products in this reaction are then reviewed, with an eye to understanding the reaction's mechanism and how reactant structure controls rates and equilibria in the process. Recent work that has uncovered structural features and new mechanisms for speeding the reaction, sometimes by orders of magnitude, is discussed. We describe recent studies that have identified especially fast reacting aldehyde/ketone substrates and structural effects that lead to rapid-reacting α-nucleophiles as well. Among the most effective new strategies has been the development of substituents near the reactive aldehyde group that either transfer protons at the transition state or trap the initially formed tetrahedral intermediates. In addition, the recent development of efficient nucleophilic catalysts for the reaction is outlined, improving greatly upon aniline, the classical catalyst for imine formation. A number of uses of such second- and third-generation catalysts in bioconjugation and in cellular applications are highlighted. While formation of hydrazone and oxime has been traditionally regarded as being limited by slow rates, developments in the past 5 years have resulted in completely overturning this limitation; indeed, the reaction is now one of the fastest and most versatile reactions available for conjugations of biomolecules and biomaterials.
Topics: Biocompatible Materials; Catalysis; Hydrazones; Imines; Molecular Structure; Oximes
PubMed: 28640998
DOI: 10.1021/acs.chemrev.7b00090 -
Molecules (Basel, Switzerland) Jan 2016Oxime derivatives are easily made, are non-hazardous and have long shelf lives. They contain weak N-O bonds that undergo homolytic scission, on appropriate thermal or... (Review)
Review
Oxime derivatives are easily made, are non-hazardous and have long shelf lives. They contain weak N-O bonds that undergo homolytic scission, on appropriate thermal or photochemical stimulus, to initially release a pair of N- and O-centred radicals. This article reviews the use of these precursors for studying the structures, reactions and kinetics of the released radicals. Two classes have been exploited for radical generation; one comprises carbonyl oximes, principally oxime esters and amides, and the second comprises oxime ethers. Both classes release an iminyl radical together with an equal amount of a second oxygen-centred radical. The O-centred radicals derived from carbonyl oximes decarboxylate giving access to a variety of carbon-centred and nitrogen-centred species. Methods developed for homolytically dissociating the oxime derivatives include UV irradiation, conventional thermal and microwave heating. Photoredox catalytic methods succeed well with specially functionalised oximes and this aspect is also reviewed. Attention is also drawn to the key contributions made by EPR spectroscopy, aided by DFT computations, in elucidating the structures and dynamics of the transient intermediates.
Topics: Amides; Carbon; Electron Spin Resonance Spectroscopy; Esters; Ethers; Free Radicals; Hot Temperature; Microwaves; Oximes; Photochemical Processes; Quantum Theory; Reactive Nitrogen Species; Reactive Oxygen Species; Ultraviolet Rays
PubMed: 26751437
DOI: 10.3390/molecules21010063 -
Bioorganic & Medicinal Chemistry Oct 2018New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ-THC. The scope of the research...
New oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ-THC. The scope of the research was to drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.5-3.5 vs 9.09 of Δ-THC-DMH), and found to function as either agonists (trans-oximes) or neutral antagonists (cis-oximes) in a cAMP functional assay. All oxime analogs showed comparable affinity at the CB2 receptor, but surprisingly they were found to function as inverse agonists for CB2. In behavioral studies (i.e. analgesia, hypothermia) trans-oxime 8a exhibited a predictable fast onset (∼20 min) and short duration of pharmacological action (∼180 min), in contrast to the very prolonged duration of Δ-THC-DMH (>24 h), thus limiting the potential for severe psychotropic side-effects associated with persistent activation of the CB1 receptor. We have conducted 100 ns molecular dynamic (MD) simulations of CB1 complexes with AM11542 (CB1 agonist) and both trans-8a and cis-8b isomeric oximes. These studies revealed that the C3 alkyl tail of cis-8b orientated within the CB1 binding pocket in a manner that triggered a conformational change that stabilized the CB1 receptor at its inactive-state (antagonistic functional effect). In contrast, the trans-8a isomer's conformation was coincided with that of the AM11542 CB1 agonist-bound structure, stabilizing the CB1 receptor at the active-state (agonistic functional effect). We have selected oxime trans-8a based on its potency for CB1, and favorable pharmacodynamic profile, such as fast onset and predictable duration of pharmacological action, for evaluation in pre-clinical models of anorexia nervosa.
Topics: Analgesics; Animals; Area Under Curve; Behavior, Animal; Biotransformation; HEK293 Cells; Humans; Hypothermia; Mice; Oximes; Rats; Receptor, Cannabinoid, CB1; Structure-Activity Relationship
PubMed: 30122284
DOI: 10.1016/j.bmc.2018.08.003 -
Journal of Agricultural and Food... Jul 2023Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel...
Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel mode of action. Using antiviral alkaloid aldisine as the lead compound and drawing on the hydrogen bond effect widely used in drug design, derivatives containing oxime and hydrazone moieties were designed and synthesized by introducing functional groups with hydrogen-bond receptors or donors into molecules. The configuration of derivatives was systematically studied through nuclear Overhauser effect (NOE) spectroscopy and single crystal analysis. The antiviral activity test result showed that most derivatives had antiviral activity against tobacco mosaic virus (TMV), and some compounds had better activity than the commercial antiviral drug ribavirin, especially compounds and , which had comparable activity to the most effective commercial antiviral drug ningnanmycin. Preliminary mode of action studies showed that compound could affect the assembly of rod-shaped TMVs by promoting the aggregation and fragmentation of TMV coat proteins. Molecular docking experiments demonstrated that the introduction of oxime and hydrazone moieties could indeed increase the hydrogen bond between molecules and target proteins. In addition, we conducted fungicidal and larvicidal activities study of these derivatives. Most of these derivatives had good larvicidal activities against and and showed broad-spectrum fungicidal activities.
Topics: Structure-Activity Relationship; Molecular Structure; Oximes; Molecular Docking Simulation; Hydrogen Bonding; Tobacco Mosaic Virus; Antiviral Agents; Hydrazines; Hydrazones; Drug Design
PubMed: 37442997
DOI: 10.1021/acs.jafc.3c02480