-
Annals of the New York Academy of... Aug 2016Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and... (Review)
Review
Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus.
Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Crystallography, X-Ray; Drug Design; Humans; Organophosphate Poisoning; Oximes; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 27371941
DOI: 10.1111/nyas.13128 -
Molecules (Basel, Switzerland) May 2021The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal...
The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.
Topics: Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA; Estrogen Receptor alpha; Estrogens; Estrone; Fluorouracil; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Oximes
PubMed: 34064380
DOI: 10.3390/molecules26092687 -
Toxicology Aug 2018The antidotal property of oximes is attributed to their ability to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP) such as pesticides...
The antidotal property of oximes is attributed to their ability to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OP) such as pesticides and nerve warfare agents. Understanding their interactions within the active site of phosphylated AChE is of great significance for the search for more efficient reactivators, especially in the case of the most resistant OP to reactivation, tabun. Therefore, herein we studied the interactions and reactivation of tabun-inhibited AChE by site-directed mutagenesis and a series of bispyridinium oximes. Our results indicated that the replacement of aromatic residues with aliphatic ones at the acyl pocket and choline binding site mostly interfered with the stabilisation of the oxime's pyridinium ring(s) within the active site gorge needed to obtain the proper orientation of the oxime group toward the phosphorylated active site serine. However, in the case of W286A, the mutation in the peripheral binding site by preventing a π-π interaction with one of the oxime's pyridinium rings allowed a more favourable position of the oxime for a nucleophilic attack on the phosphorylated catalytic serine. The mutation resulted in a 2-5 fold increase in the reactivation rates when compared to the AChE wild type. Therefore, it seems that aromatic amino acids at the peripheral binding site presented a limitation in bispyridinium oxime reactivation efficiency of tabun-phosphorylated AChE. Moreover, this is further corroborated by the reactivation by mono-pyridinium oxime 2-PAM, in which mutations at the peripheral site did not influence either the affinity or reactivation of tabun-inhibited AChE.
Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Mice; Molecular Docking Simulation; Mutation; Organophosphates; Oximes
PubMed: 29772260
DOI: 10.1016/j.tox.2018.05.008 -
Chemical Reviews Aug 2011
Review
Topics: Cyclization; Ethers; Heterocyclic Compounds; Oxidation-Reduction; Oximes
PubMed: 21434602
DOI: 10.1021/cr100292w -
Journal of Medicinal Chemistry Jul 2021Screening of a library of small polar molecules against () led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected...
Screening of a library of small polar molecules against () led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated for pharmacokinetic properties. -mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
Topics: Antitubercular Agents; Carbamates; Dose-Response Relationship, Drug; Heterocyclic Compounds; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Oximes; Structure-Activity Relationship
PubMed: 34138573
DOI: 10.1021/acs.jmedchem.1c00707 -
Chemical & Pharmaceutical Bulletin 2014The application of conjugated oxime ethers to the synthesis of complex chemical scaffolds using domino radical reactions has been described in detail. The... (Review)
Review
The application of conjugated oxime ethers to the synthesis of complex chemical scaffolds using domino radical reactions has been described in detail. The triethylborane-mediated hydroxysulfenylation reaction allows for the regioselective construction of a carbon-sulfur bond and a carbon-oxygen bond in a single operation for the formation of β-hydroxy sulfides. This reaction proceeds via a radical pathway involving regioselective thiyl addition and the subsequent trapping of the resulting α-imino radical with O₂, where the imino group enhances the stability of the intermediate radical. Hydroxyalkylation reactions that occur via a carbon radical addition reaction followed by the hydroxylation of the resulting N-borylenamine with O₂ have also been developed. We investigated sequential radical addition aldol-type reactions in detail to explore the novel domino reactions that occur via the generation of N-borylenamine. The radical reaction of a conjugated oxime ether with triethylborane in the presence of an aldehyde affords γ-butyrolactone via sequential processes including ethyl radical addition, the generation of N-borylenamine, an aldol-type reaction with an aldehyde, and a lactonization reaction. A novel domino reaction has also been developed involving the [3,3]-sigmatropic rearrangement of N-boryl-N-phenoxyenamine. The triethylborane-mediated domino reactions of O-phenyl-conjugated oxime ethers afforded the corresponding benzofuro[2,3-b]pyrrol-2-ones via a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade.
Topics: Ethers; Free Radicals; Oximes
PubMed: 25177013
DOI: 10.1248/cpb.c14-00388 -
Organic Letters Nov 2020Hydrazone and oxime peptide ligations are catalyzed by arginine. The catalysis is assisted intramolecularly by the side-chain guanidinium group. Hydrazone ligation in...
Hydrazone and oxime peptide ligations are catalyzed by arginine. The catalysis is assisted intramolecularly by the side-chain guanidinium group. Hydrazone ligation in the presence of arginine proceeds efficiently in phosphate buffer at neutral pH but is particularly powerful in bicarbonate/CO buffer. In addition to acting as a catalyst, arginine prevents the aggregation of proteins during ligation. With its dual properties as a nucleophilic catalyst and a protein aggregation inhibitor, arginine hydrochloride is a useful addition to the hydrazone/oxime ligation toolbox.
Topics: Arginine; Catalysis; Hydrazones; Hydrogen-Ion Concentration; Oximes; Peptides
PubMed: 33104364
DOI: 10.1021/acs.orglett.0c03195 -
European Journal of Medicinal Chemistry Aug 2022The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human...
The fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pK of the oxime group (fluorinated < chlorinated < non-halogenated) along with higher level of oximate anion formation at the physiological pH, and had a higher binding affinity of both AChE and BChE. The stability tests showed that the fluorinated oximes were stable in water, while in buffered environment di-fluorinated oximes were prone to rapid degradation, which was reflected in their lower reactivation ability. Mono-fluorinated oximes showed comparable reactivation to non-halogenated (except asoxime) and mono-chlorinated oximes in case of AChE inhibited by sarin, cyclosarin, VX, and tabun, but were less efficient than di-chlorinated ones. The same trend was observed in the reactivation of inhibited BChE. The advantage of halogen substituents in the stabilization of oxime in a position optimal for in-line nucleophilic attack were confirmed by extensive molecular modelling of pre-reactivation complexes between the analogue oximes and phosphorylated AChE and BChE. Halogen substitution was shown to provide oximes with additional beneficial properties, e.g., fluorinated oximes gained antioxidative capacity, and moreover, halogens themselves did not increase cytotoxicity of oximes. Finally, the in vivo administration of highly efficient reactivator and the most promising analogue, 3,5-di-chloro-bispyridinium oxime with trimethylene linker, provided significant protection of mice exposed to sarin and cyclosarin.
Topics: Acetylcholinesterase; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Halogens; Mice; Nerve Agents; Organophosphorus Compounds; Oximes; Sarin
PubMed: 35526478
DOI: 10.1016/j.ejmech.2022.114377 -
Organic & Biomolecular Chemistry Jan 2022Seventeen C20--alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC...
Seventeen C20--alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20--alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Conformation; Oximes; Pyrans
PubMed: 35006233
DOI: 10.1039/d1ob02292j -
Toxicological Sciences : An Official... Jun 2019Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel...
Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel substituted phenoxyalkyl pyridinium oximes have previously shown evidence of penetrating the rat blood-brain barrier (BBB) in in vivo tests with a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the active metabolite of the insecticide parathion, paraoxon (PXN), by reducing the time to cessation of seizure-like behaviors and accumulation of glial fibrillary acidic protein, whereas 2-PAM did not. The neuroprotective ability of our lead oximes (15, 20, and 55) was tested using NeuN, Nissl, and Fluoro-Jade B staining in the rat hippocampus. Following lethal-level subcutaneous challenge with NIMP or PXN, rats were intramuscularly administered a novel oxime or 2-PAM plus atropine and euthanized at 4 days. There were statistically significant increases in the median damage scores of the NeuN-stained NIMP, NIMP/2-PAM, and NIMP/Oxime 15 groups compared with the control whereas the scores of the NIMP/Oxime 20 and NIMP/Oxime 55 were not significantly different from the control. The same pattern of statistical significance was observed with PXN. Nissl staining provided a similar pattern, but without statistical differences. Fluoro-Jade B indicated neuroprotection from PXN with novel oximes but not with 2-PAM. The longer blood residence times of Oximes 20 and 55 compared with Oxime 15 might have contributed to their greater efficacy. These results suggest that novel oximes 20 and 55 were able to penetrate the BBB and attenuate neuronal damage after NIMP and PXN exposure, indicating potential broad-spectrum usefulness.
Topics: Animals; Blood-Brain Barrier; Cholinesterase Reactivators; Hippocampus; Male; Neuroprotective Agents; Organophosphates; Oximes; Rats; Rats, Sprague-Dawley
PubMed: 30835286
DOI: 10.1093/toxsci/kfz060