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The Journal of Physical Chemistry. B Mar 2007Oximes (especially oximate anions) are used as potential reactivators of OP-inhibited AChE due to their unique alpha-effect nucleophilic reactivity. In the present...
Oximes (especially oximate anions) are used as potential reactivators of OP-inhibited AChE due to their unique alpha-effect nucleophilic reactivity. In the present study, by applying the DFT approach at the B3LYP/6-311G(d,p) level and the Møller-Plesset perturbation theory at the MP2/6-311G(d,p) level, the formoximate-induced reactivation patterns of the sarin-AChE adduct and the corresponding reaction mechanism have been investigated. The potential energy surface along the pathway of the reactivation reaction of sarin-inhibited AChE by oxime reveals that the reaction can occur quickly due to the relatively low energy barriers. A two-step process is a major pathway proposed for the studied reactivation reaction. Through the nucleophilic attack, the oximate first binds to the sarin-AChE adduct to form a relatively stable phosphorus complex. The regeneration of the serine takes place subsequently through an elimination step, which is expected to be competitive with the nucleophilic attacking process. The polarizable continuum model (PCM) has been applied to evaluate the solvate effects on the pathway. It is concluded that the reaction energy barriers are also low enough for the reaction to easily occur in solvent. The results derived from both the gas-phase model and the aqueous solvation model suggest that the studied oximate anion is an efficient antidote reagent for sarin-inhibited AChE.
Topics: Acetylcholinesterase; Anions; Biophysics; Chemistry, Physical; Enzyme Activation; Enzyme Reactivators; Kinetics; Models, Chemical; Models, Molecular; Models, Theoretical; Oximes; Sarin; Solvents; Temperature; Thermodynamics
PubMed: 17298091
DOI: 10.1021/jp067741s -
Chemico-biological Interactions Mar 2013Administration of oxime therapy is currently the standard approach used to reverse the acute toxicity of organophosphorus (OP) compounds, which is usually attributed to...
Administration of oxime therapy is currently the standard approach used to reverse the acute toxicity of organophosphorus (OP) compounds, which is usually attributed to OP inhibition of acetylcholinesterase (AChE). Rate constants for reactivation of OP-inhibited AChE by even the best oximes, such as HI-6 and obidoxime, can vary >100-fold between OP-AChE conjugates that are easily reactivated and those that are difficult to reactivate. To gain a better understanding of this oxime specificity problem for future design of improved reactivators, we conducted a QSAR analysis for oxime reactivation of AChE inhibited by OP agents and their analogues. Our objective was to identify common mechanism(s) among OP-AChE conjugates of phosphates, phosphonates and phosphoramidates that result in resistance to oxime reactivation. Our evaluation of oxime reactivation of AChE inhibited by a sarin analogue, O-methyl isopropylphosphonofluoridate, or a cyclosarin analogue, O-methyl cyclohexylphosphonofluoridate, indicated that AChE inhibited by these analogues was at least 70-fold more difficult to reactivate than AChE inhibited by sarin or cyclosarin. In addition, AChE inhibited by an analogue of tabun (i.e., O-ethyl isopropylphosphonofluoridate) was nearly as resistant to reactivation as tabun-inhibited AChE. QSAR analysis of oxime reactivation of AChE inhibited by these OP compounds and others suggested that the presence of both a large substituent (i.e., ≥ the size of dimethylamine) and an alkoxy substituent in the structure of OP compounds is the common feature that results in resistance to oxime reactivation of OP-AChE conjugates whether the OP is a phosphate, phosphonate or phosphoramidate.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; GPI-Linked Proteins; Humans; Kinetics; Obidoxime Chloride; Organophosphorus Compounds; Oximes; Pyridinium Compounds; Quantitative Structure-Activity Relationship; Recombinant Proteins; Sarin
PubMed: 22982773
DOI: 10.1016/j.cbi.2012.08.024 -
Bioconjugate Chemistry Mar 2013Imine-based reactions are useful for a wide range of bioconjugation applications. Although aniline is known to catalyze the oxime ligation reaction under physiological...
Imine-based reactions are useful for a wide range of bioconjugation applications. Although aniline is known to catalyze the oxime ligation reaction under physiological conditions, it suffers from slow reaction kinetics, specifically when a ketone is being used or when hydrazone-oxime exchange is performed. Here, we report on the discovery of a new catalyst that is up to 15 times more efficient than aniline. That catalyst, m-phenylenediamine (mPDA), was initially used to analyze the kinetics of oxime ligation on aldehyde- and ketone-containing small molecules. While mPDA is only modestly more effective than aniline when used in equal concentrations (~2-fold), its much greater aqueous solubility relative to aniline allows it to be used at higher concentrations, resulting in significantly more efficient catalysis. In the context of protein labeling, it was first used to site-specifically label an aldehyde-functionalized protein through oxime ligation, and its kinetics were compared to reaction with aniline. Next, a protein was labeled with an aldehyde-containing substrate in crude cell lysate, captured with hydrazide-functionalized beads and then the kinetics of immobilized protein release via hydrazone-oxime exchange were analyzed. Our results show that mPDA can release and label 15 times more protein than aniline can in 3 h. Then, using the new catalyst, ciliary neurotrophic factor, a protein with therapeutic potential, was successfully labeled with a fluorophore in only 5 min. Finally, a protein containing the unnatural amino acid, p-acetyl phenylalanine, a ketone-containing residue, was prepared and PEGylated efficiently via oxime ligation using mPDA. This new catalyst should have a significant impact on the field of bioconjugation, where oxime ligation and hydrazone-oxime exchange are commonly employed.
Topics: Catalysis; Hydrazones; Oximes; Phenylenediamines
PubMed: 23425124
DOI: 10.1021/bc3004167 -
Journal of Enzyme Inhibition and... Dec 2021The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in...
The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with Ks spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.
Topics: Amino Alcohols; Brain; Carbonic Anhydrases; Dose-Response Relationship, Drug; Ethers; Humans; Isoenzymes; Molecular Structure; Oximes; Structure-Activity Relationship
PubMed: 33103482
DOI: 10.1080/14756366.2020.1838501 -
Acta Poloniae Pharmaceutica 2015In this study, some O-benzyl (benzofuran-2-yl)ethan-1-one ether oximes were synthesized starting from 2-acetylbenzofuran. The structure elucidation of the compounds was...
In this study, some O-benzyl (benzofuran-2-yl)ethan-1-one ether oximes were synthesized starting from 2-acetylbenzofuran. The structure elucidation of the compounds was performed by IR, 1H-NMR and 13C-NMR spectra. Antimicrobial activities of the compounds were examined and notable activity was observed.
Topics: Anti-Infective Agents; Benzofurans; Ethers; Magnetic Resonance Spectroscopy; Oximes
PubMed: 26642679
DOI: No ID Found -
The Journal of Organic Chemistry Jun 2010A novel procedure has been developed for the bis-conjugation of oligonucleotides using CuAAC (click-H) and oxime (click-O) tethering strategies. Oligonucleotides bearing...
A novel procedure has been developed for the bis-conjugation of oligonucleotides using CuAAC (click-H) and oxime (click-O) tethering strategies. Oligonucleotides bearing a 5'-alkyne function and a 3'-aldehyde precursor were synthesized and were bis-conjugated with various reporters including azido carbohydrate or fluorescent dye and aminooxy peptide or carbohydrate. Versatility of the method was demonstrated by performing click-O prior to click-H and vice versa. Interestingly, when click-O is achieved prior to click-H, no purification is required in between, allowing a sequential one-pot protocol.
Topics: Copper; Methods; Molecular Probes; Oligonucleotides; Organic Chemistry Phenomena; Oximes
PubMed: 20443615
DOI: 10.1021/jo100599m -
Journal of Medicinal Chemistry Sep 1977A series of new 2-hydroxyethyl and carboxyalkyl ethers of aromatic oximes was found to possess pronounced antiinflammatory activity in the carrageenan-induced edema test...
A series of new 2-hydroxyethyl and carboxyalkyl ethers of aromatic oximes was found to possess pronounced antiinflammatory activity in the carrageenan-induced edema test in the rat. The activity was limited mainly to derivatives of p-haloacetophenone oxime and of p-halobenzaldehyde oxime. Nevertheless, the hydroxyethyl and carboxyalkyl groups may be converted into many derivatives with maintenance of activity. Some structure-activity relationships are in contrast to those of the well-known antiinflammatory arylacetic acids. The activity is limited to the E stereoisomers. The hydrochloride of 2-(dimethylamino)ethyl (E)-[[(p-chloro-alpha-methylbenzylidene)-amino[oxy]acetate (36, INN name Cloximate) was chosen for clinical evaluation. The first results agree with the pharmacological prospects.
Topics: Animals; Anti-Inflammatory Agents; Ethers; Lethal Dose 50; Mice; Oximes; Rats; Structure-Activity Relationship
PubMed: 926121
DOI: 10.1021/jm00219a018 -
Bioorganic & Medicinal Chemistry Letters Dec 2009The present work reports on the preparation of oligonucleotide conjugates via the formation of aromatic oxime linkage. The conjugation consists in the reaction between...
The present work reports on the preparation of oligonucleotide conjugates via the formation of aromatic oxime linkage. The conjugation consists in the reaction between the oligonucleotide derivatized at 5'-extremity with a benzaldehyde moiety and an aminooxy reporter group. The conjugation was found highly efficient and was extended for the conjugation of phosphorothioate oligonucleotide. In addition, the stability of the so-formed oxime conjugate was investigated.
Topics: Molecular Structure; Oligonucleotides; Oximes
PubMed: 19857965
DOI: 10.1016/j.bmcl.2009.10.048 -
Bioorganic & Medicinal Chemistry Letters Oct 2018A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and...
A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.
Topics: Amides; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Design; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Nitro Compounds; Oximes; Structure-Activity Relationship
PubMed: 30119957
DOI: 10.1016/j.bmcl.2018.07.046 -
Molecular Plant Jan 2018Oximes (RRC=NOH) are nitrogen-containing chemical constituents that are formed in species representing all kingdoms of life. In plants, oximes are positioned at... (Review)
Review
Oximes (RRC=NOH) are nitrogen-containing chemical constituents that are formed in species representing all kingdoms of life. In plants, oximes are positioned at important metabolic bifurcation points between general and specialized metabolism. The majority of plant oximes are amino acid-derived metabolites formed by the action of a cytochrome P450 from the CYP79 family. Auxin, cyanogenic glucosides, glucosinolates, and a number of other bioactive specialized metabolites including volatiles are produced from oximes. Oximes with the E configuration have high biological activity compared with Z-oximes. Oximes or their derivatives have been demonstrated or proposed to play roles in growth regulation, plant defense, pollinator attraction, and plant communication with the surrounding environment. In addition, oxime-derived products may serve as quenchers of reactive oxygen species and storage compounds for reduced nitrogen that may be released on demand by the activation of endogenous turnover pathways. As highly bioactive molecules, chemically synthesized oximes have found versatile uses in many sectors of society, especially in the agro- and medical sectors. This review provides an update on the structural diversity, occurrence, and biosynthesis of oximes in plants and discusses their role as key players in plant general and specialized metabolism.
Topics: Animals; Lizards; Oximes; Plants; Volatile Organic Compounds
PubMed: 29275165
DOI: 10.1016/j.molp.2017.12.014