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Molecules (Basel, Switzerland) May 2020The pyridinium oximes are known esterolytic agents, usually classified in the literature as catalysts, which mimic the catalytic mode of hydrolases. Herein, we combined...
The pyridinium oximes are known esterolytic agents, usually classified in the literature as catalysts, which mimic the catalytic mode of hydrolases. Herein, we combined kinetic and computational studies of the pyridinium-4-oxime-mediated acetylthiocholine (AcSCh) hydrolysis to provide novel insights into their potential catalytic activity. The -methyl- and -benzylpyridinium-4-oximes have been tested as oximolytic agents toward the AcSCh, while the newly synthesized -acetyl--methylpyridinium-4-oxime iodide was employed for studying the consecutive hydrolytic reaction. The relevance of the AcSCh hydrolysis as a competitive reaction to AcSCh oximolysis was also investigated. The reactions were independently studied spectrophotometrically and rate constants, , and , were evaluated over a convenient pH-range at = 0.1 M and 25 °C. The catalytic action of pyridinium-4-oximes comprises two successive stages, acetylation (oximolysis) and deacetylation stage (pyridinium-4-oxime-ester hydrolysis), the latter being crucial for understanding the whole catalytic cycle. The complete mechanism is presented by the free energy reaction profiles obtained with (CPCM)/M06-2X/6-311++G(2df,2pd)//(CPCM)/M06-2X/6-31+G(d) computational model. The comparison of the observed rates of AcSCh oximolytic cleavage and both competitive AcSCh and consecutive pyridinium-4-oxime-ester hydrolytic cleavage revealed that the pyridinium-4-oximes cannot be classified as non-enzyme catalyst of the AcSCh hydrolysis but as the very effective esterolytic agents.
Topics: Acetylthiocholine; Catalysis; Cholinesterase Inhibitors; Cholinesterase Reactivators; Computational Chemistry; Humans; Kinetics; Oximes; Pyridinium Compounds
PubMed: 32455554
DOI: 10.3390/molecules25102385 -
Molecules (Basel, Switzerland) Jun 2020Protein-protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended... (Review)
Review
Protein-protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined "hot spot" regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Unfortunately, contacts afforded by the 20 natural amino acids may be suboptimal and inefficient for accessing both canonical binding interactions and transient "cryptic" binding pockets. Oxime ligation represents a class of biocompatible "click" chemistry that allows the structural diversity of libraries of aldehydes to be rapidly evaluated within the context of a parent oxime-containing peptide platform. Importantly, oxime ligation represents a form of post solid-phase diversification, which provides a facile and empirical means of identifying unanticipated protein-peptide interactions that may substantially increase binding affinities and selectivity. The current review will focus on the authors' use of peptide ligation to optimize PPI antagonists directed against several targets, including tumor susceptibility gene 101 (Tsg101), protein tyrosine phosphatases (PTPases) and the polo-like kinase 1 (Plk1). This should provide insights that can be broadly directed against an almost unlimited range of physiologically important PPIs.
Topics: Cell Cycle Proteins; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; Humans; Oximes; Peptides; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Transcription Factors; Polo-Like Kinase 1
PubMed: 32570752
DOI: 10.3390/molecules25122807 -
Methods in Molecular Biology (Clifton,... 2024The large variety and high concentration of O-glycans are characteristic properties of mucins and play a crucial role in their unique functions. Analyzing the O-glycans...
The large variety and high concentration of O-glycans are characteristic properties of mucins and play a crucial role in their unique functions. Analyzing the O-glycans of mucins is essential for investigating the functions of mucins. Eliminative oximation is an aqueous reaction that can be used to obtain O-glycan oximes from mucins. Using diazabicyclo undec-7ene (DBU) as a base, an organic superbase that can be removed with an organic solvent during solid-phase extraction, and adding hydroxylamine to the reaction mixture in advance, the O-glycans released from the mucin are immediately converted to the corresponding glycan oximes. The glycan oxime can then be fluorescently labeled with a fluorescent labeling reagent and 2-picoline borane via reductive amination. O-glycans that have been fluorescently labeled can be analyzed using conventional HPLC techniques.
Topics: Mucins; Chromatography, High Pressure Liquid; Hydroxylamine; Oximes; Polysaccharides
PubMed: 38347408
DOI: 10.1007/978-1-0716-3670-1_13 -
Recent advances in cholinergic mechanisms as reactions to toxicity, stress, and neuroimmune insults.Journal of Neurochemistry Apr 2024This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators... (Review)
Review
This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter-change under acute states, age, sex, and COVID-19 infection; all of which modulate ACh-mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime-assisted reactivation of inhibited AChE. The over-arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti-cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long-term deleterious effects of OPs.
Topics: Female; Humans; Cholinesterase Reactivators; Cholinesterase Inhibitors; Acetylcholinesterase; Organophosphorus Compounds; Oximes; Acetylcholine; RNA
PubMed: 37429600
DOI: 10.1111/jnc.15887 -
Neuropharmacology Sep 2020This review provides an overview of the global research leading to the large number of compounds developed as reactivators of acetylcholinesterase inhibited by a variety... (Review)
Review
This review provides an overview of the global research leading to the large number of compounds developed as reactivators of acetylcholinesterase inhibited by a variety of organophosphate compounds, most of which are nerve agents but also some insecticides. A number of these organophosphates are highly toxic and effective therapy by reactivators contributes to saving lives. Two major challenges for more effective therapy with reactivators are identification of a broad spectrum reactivator efficacious against a variety of organophosphate structures, and a reactivator that can cross the blood-brain barrier to protect the brain. The most effective of the reactivators developed are the nucleophilic pyridinium oximes, which bear a permanent positive charge from the quaternary nitrogen in the pyridinium ring. The permanent positive charge retards the oximes from crossing the blood-brain barrier and therefore restoration of normal cholinergic function in the brain is unlikely. A number of laboratories have developed nucleophiles, mostly oximes, that are theorized to cross the blood-brain barrier by several strategies. At the present time, no reactivator is optimally broad spectrum across the wide group of organophosphate chemistries. Some oximes, including the substituted phenoxyalkyl pyridinium oximes invented by our laboratories, have the potential to provide neuroprotection in the brain and show evidence of efficacy against both nerve agent and insecticidal chemistries, so these novel oximes have promise for future development. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
Topics: Acetylcholinesterase; Animals; Brain; Cholinesterase Inhibitors; Humans; Mice; Organophosphonates; Oximes
PubMed: 32544483
DOI: 10.1016/j.neuropharm.2020.108201 -
Bioorganic & Medicinal Chemistry Sep 2021Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer...
Steroidal compounds were proven to be efficient drugs against several types of cancer. Oximes are also chemical structures frequently associated with anticancer activity. The main goal of this work was to combine the two referred structures by synthesizing steroidal oximes and evaluating them in several cancer cell lines. Compounds (17E)-5α-androst-3-en-17-one oxime (3,4 - OLOX), (17E)-3α,4α-epoxy-5α-androstan-17-one oxime (3,4 - EPOX), (17E)-androst-4-en-17-one oxime (4,5 - OLOX) and (17E)-4α,5α-epoxyandrostan-17-one oxime (4,5 - EPOX) were synthesized and their cytotoxicity evaluated in four human cancer cell lines, namely colorectal adenocarcinoma (WiDr), non-small cell lung cancer (H1299), prostate cancer (PC3) and hepatocellular carcinoma (HepG2). A human non-tumour cell line, CCD841 CoN (normal colon cell line) was also used. MTT assay, flow cytometry, fluorescence and hemocompatibility techniques were performed to further analyse the cytotoxicity of the compounds. 3,4 - OLOX was the most effective compound in decreasing tumour cell proliferation in all cell lines, especially in WiDr (IC = 9.1 μM) and PC3 (IC = 13.8 μM). 4,5 - OLOX also showed promising results in the same cell lines (IC = 16.1 μM in WiDr and IC = 14.5 μM in PC3). Further studies also revealed that 3,4 - OLOX and 4,5 - OLOX induced a decrease in cell viability accompanied by an increase in cell death, mainly by apoptosis/necroptosis for 3,4 - OLOX in both cell lines and for 4,5 - OLOX in WiDr cells, and by necrosis for 4,5 - OLOX in PC3 cells. These compounds might also exert their cytotoxicity by ROS production and are not toxic for non-tumour CCD841 CoN cells. Additionally, both compounds did not induce haemoglobin release, proving to be safe for intravenous administration. 3,4 - OLOX and 4,5 - OLOX might be the starting point for an optimization program towards the discover of new steroidal oximes for anticancer treatment.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Oxidative Stress; Oximes; Steroids; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 34425478
DOI: 10.1016/j.bmc.2021.116360 -
Toxicology and Applied Pharmacology Mar 2021The brain is a critical target for the toxic action of organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) such as the nerve agent sarin. However, the... (Comparative Study)
Comparative Study
The tertiary oxime monoisonitrosoacetone penetrates the brain, reactivates inhibited acetylcholinesterase, and reduces mortality and morbidity following lethal sarin intoxication in guinea pigs.
The brain is a critical target for the toxic action of organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) such as the nerve agent sarin. However, the available oxime antidote 2-PAM only reactivates OP-inhibited AChE in peripheral tissues. Monoisonitrosoacetone (MINA), a tertiary oxime, reportedly reactivates AChE in the central nervous system (CNS). The current study investigated whether MINA would be beneficial as a supplemental oxime treatment in preventing lethality and reducing morbidity following lethal sarin exposure, MINA supplement would improve AChE recovery in the body, and MINA would be detectable in the CNS. Guinea pigs were exposed to sarin and treated with atropine sulfate and 2-PAM at one minute. Additional 2-PAM or MINA was administered at 3, 5, 15, or 30 min after sarin exposure. Survival and morbidity were assessed at 2 and 24 h. AChE activity in brain and peripheral tissues was evaluated one hour after MINA and 2-PAM treatment. An in vivo microdialysis technique was used to determine partitioning of MINA into the brain. A liquid chromatography-tandem mass spectrometry method was developed for the analysis of MINA in microdialysates. MINA-treated animals exhibited significantly higher survival and lower morbidity compared to 2-PAM-treated animals. 2-PAM was significantly more effective in reactivating AChE in peripheral tissues, but only MINA reactivated AChE in the CNS. MINA was found in guinea pig brain microdialysate samples beginning at ~10 min after administration in a dose-related manner. The data strongly suggest that a centrally penetrating oxime could provide significant benefit as an adjunct to atropine and 2-PAM therapy for OP intoxication.
Topics: Acetylcholinesterase; Animals; Antidotes; Brain; Cholinesterase Reactivators; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Guinea Pigs; Male; Microdialysis; Organophosphate Poisoning; Oximes; Permeability; Pralidoxime Compounds; Sarin; Tissue Distribution
PubMed: 33548273
DOI: 10.1016/j.taap.2021.115443 -
Molecules (Basel, Switzerland) Mar 2020Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme...
AIMS
Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome.
METHODS
Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure.
RESULTS
Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens.
CONCLUSIONS
Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
Topics: Animals; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Organophosphates; Oximes; Paraoxon; Physostigmine; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Proportional Hazards Models; Pyridostigmine Bromide; Ranitidine; Rats; Rats, Wistar; Survival Analysis; Tacrine
PubMed: 32230733
DOI: 10.3390/molecules25071521 -
Molecules (Basel, Switzerland) Sep 2023New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds and ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic...
Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.
New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds and ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds -, -, -, and -. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds , , , and inhibited EGFR with IC values ranging from 8 to 21 µM when compared with sorafenib. Compound inhibited JNK-2 as effectively as sorafenib, with an IC of 1.0 µM. Furthermore, compound showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds , , , and exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds and had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.
Topics: Humans; Molecular Docking Simulation; Sorafenib; Structure-Activity Relationship; HeLa Cells; Oximes; Cell Line, Tumor; Antineoplastic Agents; ErbB Receptors; Cell Proliferation; Molecular Structure; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors
PubMed: 37764297
DOI: 10.3390/molecules28186521 -
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