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The Journal of Organic Chemistry Mar 2010Chemoselective formation of glycoconjugates from unprotected glycans is needed to further develop chemical biology involving glycans. Carbohydrate oxime formation is...
Chemoselective formation of glycoconjugates from unprotected glycans is needed to further develop chemical biology involving glycans. Carbohydrate oxime formation is often slow, and organocatalysis by anilines would be highly promising. Here, we present that carbohydrate oxime formation can be catalyzed with up to 20-fold increases in overall reaction rate at 100 mM aniline. Application of this methodology provided access to complex glycoconjugates.
Topics: Aniline Compounds; Carbohydrates; Catalysis; Glycoconjugates; Magnetic Resonance Spectroscopy; Models, Chemical; Molecular Sequence Data; Molecular Structure; Oximes; Polysaccharides
PubMed: 20131837
DOI: 10.1021/jo902425v -
Bioorganic Chemistry Jul 2020A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this...
A new series of novel nonquaternary conjugates and non-oxime reactivators for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. Conjugates with piperazine linked to the substituted salicylaldoxime emerged as efficient reactivators for VX inhibited hAChE. The in vitro reactivation experiment showed that some of them were equal or more efficient reactivators for pesticides inhibited hAChE than obidoxime. It was also found that some non-oxime derivatives of Mannich phenols displayed obvious reactivation potency for VX, sarin and pesticides inhibited hAChE even in very low concentration. It has been proved that introduction of peripheral site ligands with widespread aromatic system and amide substitutions could increase binding affinity for inhibited hAChE in most cases, which contribute to the reactivation efficiency.
Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Drug Design; Humans; Kinetics; Molecular Docking Simulation; Nerve Agents; Organophosphates; Oximes; Pesticides; Piperazine
PubMed: 32388435
DOI: 10.1016/j.bioorg.2020.103902 -
European Journal of Medicinal Chemistry Jan 2019c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs...
c-Jun N-terminal kinases (JNKs) play a central role in many physiologic and pathologic processes. We synthesized novel 11H-indeno[1,2-b]quinoxalin-11-one oxime analogs and tryptanthrin-6-oxime (indolo[2,1-b]quinazoline-6,12-dion-6-oxime) and evaluated their effects on JNK activity. Several compounds exhibited sub-micromolar JNK binding affinity and were selective for JNK1/JNK3 versus JNK2. The most potent compounds were 10c (11H-indeno[1,2-b]quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime) and tryptanthrin-6-oxime, which had dissociation constants (K) for JNK1 and JNK3 of 22 and 76 nM and 150 and 275 nM, respectively. Molecular modeling suggested a mode of binding interaction at the JNK catalytic site and that the selected oxime derivatives were potentially competitive JNK inhibitors. JNK binding activity of the compounds correlated with their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation in human monocytic THP-1Blue cells and interleukin-6 (IL-6) production by human MonoMac-6 cells. Thus, oximes with indenoquinoxaline and tryptanthrin nuclei can serve as specific small-molecule modulators for mechanistic studies of JNK, as well as potential leads for the development of anti-inflammatory drugs.
Topics: Dose-Response Relationship, Drug; Humans; JNK Mitogen-Activated Protein Kinases; Models, Molecular; Molecular Structure; Oximes; Protein Kinase Inhibitors; Quinazolines; Structure-Activity Relationship
PubMed: 30347329
DOI: 10.1016/j.ejmech.2018.10.023 -
Bioorganic & Medicinal Chemistry Sep 2017Indirubin 3'-oxime (Indox (1b)) suppresses cancer cell growth (IC: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases...
Indirubin 3'-oxime (Indox (1b)) suppresses cancer cell growth (IC: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3β. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC value (1.7μM) of indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s). We found that bromine-substitution at the 5-position on 1c or any Epox/Ind derivative(s) having bromine on the aromatic ring except Epox/6'-Br-Ind was efficient to improving anticancer activity. Of the 22 Epox/Ind derivatives, 5-bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/5-Br-Ind (2c)) was the best anticancer agent in both short- (24h) (IC: 0.67μM) and extended-duration (72h) cultures. The high anticancer activity of 2c was partly due to it being a poor substrate and a suicide inhibitor for epoxide hydrolase as epoxide hydrolase was identified as the enzyme primarily responsible for the metabolism of 2c.
Topics: Antineoplastic Agents; Binding Sites; Bromine; Cell Survival; Epoxide Hydrolases; Hep G2 Cells; Humans; Indoles; Kinetics; Molecular Docking Simulation; Oximes; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 28743492
DOI: 10.1016/j.bmc.2017.07.009 -
Toxicology Letters May 2020Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating...
Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating a toxic syndrome that can be lethal if left untreated (Cannard, 2006). It is standard practice to treat Sarin (GB) intoxication with an oxime, an antimuscarinic such as atropine and an anticonvulsant. Three common oximes are available: HI-6, Pralidoxime (2-PAM) and Obidoxime (Obi), all possess a nucleophile that can break the NA-AChE covalent bond. However, each oxime's efficacy profile against various agents is different (Thiermann and Worek, 2018). In an effort to broaden therapeutic efficacy against a range of possible NA's, consideration should be given to the use of two oximes in combination. Using a guinea pig model, the first arm of this study was to determine the pharmacokinetics (PK) of HI-6 DMS, 2-PAM chloride and Obi chloride (at autoinjector equivalent doses) following intramuscular (i.m.) co-administration along with atropine to replicate either a single isometrically scaled dose (referred to in this study as a single autoinjector equivalent) of 2-PAM (and equimolar doses of Obi and HI-6) or double doses (referred to in this study as two autoinjector equivalents). The second arm of the study evaluated the efficacy of Obi and 2-PAM individually at a single or double autoinjector dose and also in combination against GB exposure. Pharmacokinetic profiles of each oxime were evaluated for both arms of the study and no significant change in parameters were reported. Improved cholinesterase reactivation was observed in a dose dependent manner with combined therapy showing similar reactivation to individual oximes alone at a two autoinjector equivalent dose. Seizure activity was reduced when combined oxime therapy was administered. This improvement was also reflected in the Racine seizure index score assigned at the end of the experimental period. To the best of our knowledge, this study is the first to evaluate and compare the pharmacokinetics of three oximes and the combination of two oximes (2-PAM and Obi) administered in naïve animals or those exposed to GB. Combined oxime therapy (Obi and 2-PAM) resulted in improved seizure control, increased cholinesterase reactivation peripherally and centrally and improved behavioral signs (Racine score). This study provides evidence that combination of oximes is effective, does not result in adverse events and that the pharmacokinetics of each oxime are not affected when administered in combination.
Topics: Acetylcholinesterase; Animals; Drug Therapy, Combination; Electrocardiography; Electroencephalography; Guinea Pigs; Male; Nerve Agents; Oximes; Sarin
PubMed: 31954867
DOI: 10.1016/j.toxlet.2020.01.013 -
Bioorganic & Medicinal Chemistry Letters Feb 2010A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide... (Comparative Study)
Comparative Study
A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide hydrolase (FAAH). In this Letter, the rationale behind the discovery and the biological evaluations of this novel class of FAAH inhibitors are presented. Both in vitro and in vivo results of selected targets are discussed, along with inhibition kinetics and molecular modeling studies.(1).
Topics: Amidohydrolases; Animals; Cannabinoid Receptor Modulators; Carbamates; Cell Line; Crystallography, X-Ray; Drug Discovery; Humans; Oximes; Protein Binding; Protein Structure, Tertiary; Rats; Signal Transduction
PubMed: 20036536
DOI: 10.1016/j.bmcl.2009.11.080 -
Organic Letters Jun 2012An N,N-carbonyl-bridged dipyrrinone oxime has been synthesized and studied as a potential sensor for organophosphates. The molecular sensor underwent a drastic...
An N,N-carbonyl-bridged dipyrrinone oxime has been synthesized and studied as a potential sensor for organophosphates. The molecular sensor underwent a drastic colorimetric response upon formation of the adduct. The pesticide dimethoate was found to produce the biggest spectral response, with a limit of detection equal to 4.0 ppm using UV-visible spectroscopy. Minimal fluorescence "turn on" via a PET mechanism was seen, and molecular modeling studies were used to explain the lower than expected PET response. The X-ray crystal structure of the fluorescent dipyrrinone oxime was also obtained.
Topics: Coloring Agents; Fluorescent Dyes; Models, Molecular; Molecular Structure; Organophosphates; Oximes; Pesticides; Positron-Emission Tomography
PubMed: 22594956
DOI: 10.1021/ol300799f -
Chemical Research in Toxicology Sep 2016There is a pressing need for new therapeutics to reactivate covalently inactivated acetylcholinesterase (AChE) due to exposure to organophosphorus (OP) compounds....
There is a pressing need for new therapeutics to reactivate covalently inactivated acetylcholinesterase (AChE) due to exposure to organophosphorus (OP) compounds. Current reactivation therapeutics (RTs) are not broad-spectrum and suffer from other liabilities, specifically the inability to cross the blood-brain-barrier. Additionally, the chemical diversity of available therapeutics is small, limiting opportunities for structure-activity relationship (SAR) studies to aid in the design of more effective compounds. In order to find new starting points for the development of oxime-containing therapeutic reactivators and to increase our base of knowledge, we have employed a combination of computational and experimental procedures to identify additional compounds with the real or potential ability to reactivate AChE while augmenting and complementing current knowledge. Computational methods were used to identify previously uninvestigated oxime-containing molecules. Experimentally, six compounds were found with reactivation capabilities comparable to, or exceeding, those of 2-pralidoxime (2-PAM) against a panel of AChE inactivated by paraoxon, diisopropylfluorophosphate (DFP), fenamiphos, and methamidophos. One compound showed enhanced reactivation ability against DFP and fenamiphos, the least tractable of these OPs to be reactivated.
Topics: Acetylcholinesterase; Computer Simulation; Databases, Chemical; Enzyme Activation; Erythrocytes; Humans; Molecular Structure; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Structure-Activity Relationship
PubMed: 27494215
DOI: 10.1021/acs.chemrestox.6b00198 -
Bioscience Reports Jun 2018The role of water in oxime-mediated reactivation of phosphylated cholinesterases (ChEs) has been asked with recurrence. To investigate oximate water structure changes in...
The role of water in oxime-mediated reactivation of phosphylated cholinesterases (ChEs) has been asked with recurrence. To investigate oximate water structure changes in this reaction, reactivation of paraoxon-inhibited human acetylcholinesterase (AChE) was performed by the oxime asoxime (HI-6) at different pH in the presence and absence of lyotropic salts: a neutral salt (NaCl), a strong chaotropic salt (LiSCN) and strong kosmotropic salts (ammonium sulphate and phosphate HPO). At the same time, molecular dynamic (MD) simulations of enzyme reactivation under the same conditions were performed over 100 ns. Reactivation kinetics showed that the low concentration of chaotropic salt up to 75 mM increased the percentage of reactivation of diethylphosphorylated AChE whereas kosmotropic salts lead only to a small decrease in reactivation. This indicates that water-breaker salt induces destructuration of water molecules that are electrostricted around oximate ions. Desolvation of oximate favors nucleophilic attack on the phosphorus atom. Effects observed at high salt concentrations (>100 mM) result either from salting-out of the enzyme by kosmotropic salts (phosphate and ammonium sulphate) or denaturing action of chaotropic LiSCN. MDs simulations of diethylphosphorylated hAChE complex with HI-6 over 100 ns were performed in the presence of 100 mM (NH)SO and 50 mM LiSCN. In the presence of LiSCN, it was found that protein and water have a higher mobility, i.e. water is less organized, compared with the ammonium sulphate system. LiSCN favors protein solvation (hydrophobic hydration) and breakage of elelectrostricted water molecules around of oximate ion. As a result, more free water molecules participated to reaction steps accompanying oxime-mediated dephosphorylation.
Topics: Acetylcholinesterase; Humans; Kinetics; Molecular Dynamics Simulation; Oximes; Phosphorylation; Water
PubMed: 29773682
DOI: 10.1042/BSR20180609 -
The Journal of Organic Chemistry Mar 2005Although salen and its analogues are versatile chelate ligands in inorganic and organometallic chemistry, synthesis of unsymmetrical salen derivatives consisting of two...
Although salen and its analogues are versatile chelate ligands in inorganic and organometallic chemistry, synthesis of unsymmetrical salen derivatives consisting of two different salicylideneimine moieties is difficult because of the C=N bond recombination. To develop stable analogues of salen-type ligands, we synthesized a series of new ligands salamo (=1,2-bis(salicylideneaminooxy)ethane) on the basis of O-alkyl oxime instead of the imine moiety. Eight salamo ligands 1a-h were prepared in 64-88% yields as colorless crystals from the corresponding salicylaldehydes 2a-h. The crystal structure of 1a-c suggests that the oxime-OH form is more predominant than the keto-NH form. The reaction of 2a-e with excess 1,2-bis(aminooxy)ethane gave monooximes 3a-e in 59-86%, which further reacted with a different salicylaldehyde to afford unsymmetrical salamo ligands 4-8 as stable crystals in 51-70%. No reaction took place when a mixture of salamo derivatives 1a and 1b was treated at 40 degrees C in H2O/MeCN (5:95). However, the metathesis reaction of salen derivatives 9a and 9b completed in 2 h to give a statistical mixture. Monooxime 3b was much more stable than monoimine 11 which is difficult to be isolated. These results indicate the extremely high stability of the salamo derivatives 1 and precursors 3.
Topics: Chelating Agents; Ethane; Ethylenediamines; Imines; Ligands; Models, Chemical; Molecular Structure; Oximes
PubMed: 15730291
DOI: 10.1021/jo048030y