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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 -
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 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2019Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical... (Review)
Review
Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical nerve agents, but more commonly, civilians are exposed to less toxic OP pesticides, resulting in the same negative toxicological effects and thousands of deaths on an annual basis. After decades of research, no new therapeutics have been realized since the mid-1900s. Upon phosphylation of the catalytic serine residue, a process known as inhibition, there is an accumulation of acetylcholine (ACh) in the brain synapses and neuromuscular junctions, leading to a cholinergic crisis and eventually death. Oxime nucleophiles can reactivate select OP-inhibited acetylcholinesterase (AChE). Yet, the fields of reactivation of AChE and butyrylcholinesterase encounter additional challenges as broad-spectrum reactivation of either enzyme is difficult. Additional problems include the ability to cross the blood brain barrier (BBB) and to provide therapy in the central nervous system. Yet another complication arises in a competitive reaction, known as aging, whereby OP-inhibited AChE is converted to an inactive form, which until very recently, had been impossible to reverse to an active, functional form. Evaluations of uncharged oximes and other neutral nucleophiles have been made. Non-oxime reactivators, such as aromatic general bases and Mannich bases, have been developed. The issue of aging, which generates an anionic phosphylated serine residue, has been historically recalcitrant to recovery by any therapeutic approach-that is, until earlier this year. Mannich bases not only serve as reactivators of OP-inhibited AChE, but this class of compounds can also recover activity from the aged form of AChE, a process referred to as resurrection. This review covers the modern efforts to address all of these issues and notes the complexities of therapeutic development along these different lines of research.
Topics: Acetylcholinesterase; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Nerve Agents; Oximes; Pesticides
PubMed: 30444932
DOI: 10.1002/chem.201805075 -
Archives of Toxicology Jul 2020Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical... (Review)
Review
Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.
Topics: Animals; Antidotes; Atropine; Cholinesterase Reactivators; Humans; Nerve Agents; Organophosphate Poisoning; Organophosphonates; Oximes; Pesticides; Treatment Outcome
PubMed: 32506210
DOI: 10.1007/s00204-020-02797-0 -
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 -
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 -
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 -
International Journal of Molecular... May 2019Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous...
Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. -butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Flavanones; HeLa Cells; Humans; MCF-7 Cells; Neoplasms; Oximes; Structure-Activity Relationship
PubMed: 31052551
DOI: 10.3390/ijms20092184 -
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