Aldoxime Group Research Articles

Photoinduced Long-Distance Hydrogen-Atom Transfer in Molecules with a 7-Hydroxyquinoline Frame and a Carbaldehyde or Aldoxime Group as the Intramolecular Hydrogen Transporting Crane.

The photochemical properties of monomeric 7-hydroxyquinoline substituted at position 8 with carbaldehyde or aldoxime groups were studied for the molecules isolated in solid Ar low-temperature matrices (at 10 K). It was experimentally demonstrated that upon UV excitation, both carbaldehyde and aldoxime groups act as intramolecular cranes transmitting hydrogen atoms from the hydroxyl group to the remote nitrogen atom of the quinoline ring. Furthermore, in the case of 7-hydroxyquinoline-8-aldoxime (and its derivatives), the second photochemical channel was activated upon UV (λ > 360 nm) excitation. This process involves syn-anti isomerization around the double C═N bond in the aldoxime group. The structures of the reactant hydroxy tautomeric form and the photoproduced isomers of the studied molecules were unequivocally determined by means of IR spectroscopy combined with theoretical predictions of the IR spectra of the candidate structures.

Wooden composite separators with ultrahigh uranium/vanadium selectivity and antibacterial property for capturing uranium from seawater

Herein, wooden composite separators with Fe3+/salicylaldoxime coatings have achieved selective extraction of uranium from seawater. The aldoxime groups inside the salicylaldoxime have been proved with excellent uranium/vanadium selectivity that the adsorption capacity ratios of uranium/vanadium are as high as 9. Moreover, the coatings could also enable the wooden separators with outstanding antibacterial properties owing to the phenolic hydroxyl groups of salicylaldoxime, making it possible for the separators to survive well in complex marine environments. The wooden separators could be further applied for practical dynamic adsorption with much lower mass resistances than typical fiber/power-based adsorbents, benefitting from the vertically aligned channels and high porosities.

Discrimination between cancerous and normal cells/tissues enabled by a near-infrared fluorescent HClO probe

A new rhodamine-aldoxime fluorescent probe was constructed, which showed a rapid fluorescence off―on response towards HClO in NIR region with ultra-low detection limit of 2.4 nM, and has successfully been utilized to distinguish cancerous from normal cells/tissues in terms of their difference in basal ROS levels. • A new NIR fluorescent HClO probe was constructed by incorporating an aldoxime reaction group into rhodamine fluorophore. • The probe showed a great and rapid off-on response towards HClO in NIR region with ultra-low detection limit. • The probe showed a great and rapid off-on response towards HClO in NIR region with ultra-low detection limit. Fluorescence-based imaging technique has widely been used to discriminate between cancerous and normal cells or tissues because of its unique merits, i.e. visualization, noninvasiveness, high-sensitivity, non-ionizing radiation, and real-time bioimaging in vivo. Such fluorescent probes are commonly designed by chemically coupling fluorophores with targeting ligands specific to overexpressed surface markers of cancer cells. However, using such probes to diagnose a diverse class of cancers is difficult because of the high heterogeneity of cancer cells. Herein, inspired by the approximately ten times higher reactive oxygen species (ROS) concentration in cancer cells than normal cells, we developed a near-infrared (NIR) fluorescent ROS probe, PyOX , by incorporating an aldoxime reaction group into rhodamine fluorophore. The probe in the mimetic physiological condition showed a great, rapid, and selective fluorescence turn―on response towards hypochlorous acid (HClO, an endogenous ROS) in near-infrared (NIR) region (λ em = 680 nm) with ultra-low detection limit of 2.4 nM, due to the HClO-triggered efficient chemical transformation of aldoxime group to nitrile oxide group. Importantly, this probe has successfully been utilized to distinguish cancer from normal cells/tissues in vitro and in vivo in terms of their difference in intracellular basal ROS levels. The present work would inspire research interest in developing more and better fluorescent ROS probes for diagnosing a wide range of cancers in clinical practice.

Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase

Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes.

Polymeric Micelles Based on Light-Responsive Block Copolymers for the Phototunable Detection of Mercury(II) Ions Modulated by Morphological Changes.

Polymeric micelles based on light-responsive block copolymers were prepared and used for the phototunable detection of mercury(II) ions. 2-Nitrobenzyl acrylate (NBA) and ( E)-2-((4-((4-formylphenyl)diazenyl)phenyl)(methyl)amino) ethyl acrylate (FPDEA) were copolymerized from a poly(ethylene oxide) (PEO) macroinitiator via atom transfer radical polymerization (ATRP), leading to a well-defined block copolymer of PEO113- b-[p(NBA10- co-FPDEA3)] with a low polydispersity index (PDI = 1.16). After polymerization, the aldehyde groups of PEO- b-[p(NBA- co-FPDEA)] were converted to aldoxime groups by reacting with hydroxylamine, leading to the formation of a final oxime-containing polymeric probe, PEO- b-[p(NBA- co-HPDEA)], P1. The resulting block copolymer, P1, was self-assembled in water to yield spherical micelles that consist of a PEO block forming a hydrophilic shell and a copolymer of light-responsive NBA and a mercury(II) ion-detecting HPDEA block forming a hydrophobic core. Upon the addition of mercury(II) ions to this micellar solution, no detection was observed since water-soluble mercury(II) ions have limited accessability to the oxime units of P1, which are located in the hydrophobic core. After UV light irradiation, however, the photolabile 2-nitrobenzyl moieties were cleaved, and hydrophobic PNBA was transformed to hydrophilic poly(acrylic acid) (PAA), leading to the photoinduced dissociation of micelles to unimers. As a result, the oxime units of P1 were exposed to a hydrophilic environment and could react with mercury(II) ions to form nitrile groups, resulting in the turn-on detection of mercury(II) ions by UV light irradiation.

A “reactive” turn-on fluorescence probe for hypochlorous acid and its bioimaging application

An aza-BODIPY-CNOH probe attached aldoxime group demonstrated the specific detection for hypochlorous acid by the turn-on red emission signal. NMR and HRMS experiments confirmed that the fluorescence originated from the oxidation degradation of the non-fluorescence, aldoxime-based aza-BODIPY-CNOH probe into the red-fluorescence, nitrile oxide-based aza-BODIPY compound aza-BODIPY-CNO. The aza-BODIPY-CNOH probe showed good biocompatibility and was low toxic to living cells as shown from MTT experiments. Living RAW264.7 cells imaging indicated the aza-BODIPY-CNOH probe had good permeability and either exogenous or endogenous HClO caused the intracellular bright-red fluorescence, showing its potential hypochlorous acid-specific sensing ability in biological systems.

A novel pyridyl triphenylamine–BODIPY aldoxime: Naked-eye visible and fluorometric chemodosimeter for hypochlorite

An aldoxime containing fluorescent probe based on vinylpydine-appended triphenylamine–BODIPY has been designed and used for hypochlorite detection. OX-PPA-BODIPY was developed by introducing an aldoxime group into the 2-position of BODIPY, which can be used for the detection of hypochlorite with a sharp color change from pink to green. The attachment of 4-vinylpyridine moiety to triphenylamine–BODIPY constructs a fluorogen with desirable conjugated system. The probe, which displays extremely weak fluorescence owing to the CN isomerization mechanism at 2-position of BODIPY, responds to HClO/ClO− through a dramatic enhancement of its fluorescence intensity. This new probe, a naked-eye visible and fluorometric chemodosimeter, exhibits high selectivity and sensitivity toward hypochlorite over other reactive oxygen species (ROS) and anions. The detection is accompanied by a 20-fold increase in fluorescent intensity (ΦF from 0.02 to 0.43). The detection limit of the probe for hypochlorite is 7.37×10−7M. Moreover, OX-PPA-BODIPY can be used to detect hypochlorite in real water samples.

Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro.

Detoxification mechanisms of the chemical warfare agent cyclosarin (GF) in presence of 6-OxP-CD were investigated in detail in in vitro model systems. Most important finding was the preference of 6-Ox-P-CD to eliminate the more toxic (-)-GF. However, elimination of GF enantiomers was dependent on the 6-OxP-CD:GF ratios showing decreasing stereoselectivity and speed of the reaction with increasing GF concentrations. Formation of covalent mono, bis, tris and tetrakis conjugates ((CHMP)n-6-OxP-CD) and appearance of small molecular fragments (SMF) as possible decomposition products after consumption of 6-OxP-CD could be observed.. Interestingly, the non-toxic metabolite O-cyclohexyl methylphosphonic acid (CHMPA) and covalent mono and bis conjugates of 6-OxP-CD and GF were immediately formed, indicating that GF elimination proceeds along different pathways. These important new insights provide information about the mode of action of 6-Ox-P-CD including the role of the pyridinium aldoxime group on the cyclodextrin ring. They are the basis for further investigations in biological media, which could eventually lead to approval of 6-OxP-CD as a new antidote against nerve agent toxicity.

Influence of the Distance Between Quaternary Nitrogen and Oxime Group on the Reactivation Ability of Oximes – Antidotes Against Nerve Agents

h olinesterase reactivators are a group of drugs originally developed as antidotes for treatment of nerve agent intoxications. Although there are five commercially available members of this group, none is considered to be a universal solution for treatment of intoxication caused by all nerve agents. Due to this, novel drug candidates are searched. To find the most promising antidotes, structure activity studies are conducted. In this contribution, distance between quaternary nitrogen and aldoxime (called oxime) group responsible for the reactivation process is discussed. For this purpose, three structurally different oxime reactivators were tested for their potency to reactivate tabun, sarin, cyclosarin and VX agent-inhibited acetylcholinesterase (A ch E; Ec 3.1.1.7). As resulted, only standard oxime reactivators with oxime group connected to the heteroaromatic ring could be considered as promising Ach E reactivators. Those with oxime group on other aromatic ring or those with quaternary nitrogen excluded from heteroarenium ring did not display any reactivation.

Detoxification of tabun at physiological pH mediated by substituted β-cyclodextrin and glucose derivatives containing oxime groups

The ability of 13 β-cyclodextrin and 2 glucose derivatives containing substituents with oxime groups as nucleophilic components to accelerate the degradation of tabun at physiological pH has been evaluated. To this end, a qualitative and a quantitative enzymatic assay as well as a highly sensitive enantioselective GC–MS assay were used. In addition, an assay was developed that provided information about the mode of action of the investigated compounds. The results show that attachment of pyridinium-derived substituents with an aldoxime group in 3- or 4-position to a β-cyclodextrin ring affords active compounds mediating tabun degradation. Activities differ depending on the structure, the number, and the position of the substituent on the ring. Highest activity was observed for a β-cyclodextrin containing a 4-formylpyridinium oxime residue in 6-position of one glucose subunit, which detoxifies tabun with a half-time of 10.2min. Comparison of the activity of this compound with that of an analog in which the cyclodextrin ring was replaced by a glucose residue demonstrated that the cyclodextrin is not necessary for activity but certainly beneficial. Finally, the results provide evidence that the mode of action of the cyclodextrin involves covalent modification of its oxime group rendering the scavenger inactive after reaction with the first tabun molecule.

Spectroscopic and structural insights into N-substituted pyridinium-4-aldoximes and their pentacyanoferrate(II) complexes

Comparative kinetic and equilibrium studies on the formation and dissociation of three mono- and one bis-pyridinium-4-aldoxime pentacyanoferrate(II) complexes have been carried out in aqueous solutions at 25°C and I=0.1M. The synthesis, spectroscopic and thermal characterization of a new N-methylpyridinium-4-aldoxime pentacyanoferrate(II) complex is presented. The obtained values for the equilibrium constants, identified as apparent formation constants (βf/M−1) along with kinetic parameters, the formation (kf/M−1s−1) and dissociation (kd/s−1) rate constants indicated the behaving of all protonated pyridinium-4-aldoximes as weak π-acceptors. The pH-dependence of the dissociation rates has been analyzed in terms of ionization abilities of the coordinated ligands. The magnitude of the dissociation rates suggested that both protonated and deprotonated ligand forms are effective σ-donors that bind to the [Fe(CN)5]3− moiety through the nitrogen atom. The deprotonation of the coordinated aldoxime group leads to the reduced lability of the complexes due to increased σ-donor capability of aldoximato nitrogen causing the strengthened of the iron(II)–nitrogen bond. The values of dissociation activation parameters, ΔH‡ and ΔS‡, are found to be consistent with the SN1 dissociative type of mechanism. The spectroscopic data (FT-IR, NMR and UV–Vis) of the isolated coordinated pentacyanoferrates(II) conforms with the weak π-acceptor properties of the pyridinium-4-aldoxime ligands. A detailed structural characterization of the iodide and chloride salt of N-methylpyridinium-4-aldoxime was also presented using NMR, FT-IR and UV–Vis spectroscopy, as well as X-ray diffraction.

The structures and stabilities of biologically active 1-phenacyl- and 1-benzoylethyl-derivatives of the pyridinium cation

Chlorides of 1-phenacylpyridinium (1), 2-methyl-1-phenacylpyridinium (2), 1-benzoylethylpyridinium (3) and 1-benzoylethylpyridinium-4-aldoxime (4) were synthesized and characterized by X-ray diffraction and by electronic absorption and NMR spectroscopies. Although declared as pharmacologically active in extracellular fluids, their stability and ionization ability as well as predominant ionic forms in aqueous environments were not clarified. Comparative electronic absorption spectral studies in aqueous media at 25°C and I=0.1M performed in this work revealed the predominance of their keto-tautomeric forms and pronounced differences in stability and ionization ability. The ionization of 1-phenacylpyridinium ions 1 and 2 with pKa values of 11.57±0.04 and 11.66±0.05, respectively produced enolates (i.e., ylides), while the subsequent base-catalyzed first-order decomposition occurred via hydrate zwitterion and produced the benzoate ion and the corresponding 1-methylpyridinium derivative. A different proximate cause of the ascertained instabilities of the 1-benzoylethylpyridinium compounds (3 and 4) was determined. The base-catalyzed establishment of the ketone to gem-diol equilibrium of 3 was found to have a hydration constant smaller than 0.01. Compound 4 underwent a base-catalyzed breakdown due to the instability of its enolate form which resulted in the formation of a pyridine-4-aldoxime and phenyl vinyl ketone. Ionization constants of 3 and 4 keto-forms were estimated as the lowest possible pKa values of 12, while the pKa value of pyridinium aldoxime group of 4 was found to be 8.51±0.04. The identified stabilities and ionization abilities of these compounds were additionally supported by their presented coordination ability toward the iron(II) in the pentacyanoferrate(II) moiety.

Oxime Decorated Cavitands Functionalized through Solvent-Assisted Grinding

In order to assemble supramolecular capsules, there is a need for reliable and effective synthetic methods for decorating cavitand-based host structures with appropriate functional groups. The synthesis of four different cavitands of significantly different depth and interior volume functionalized with four aldoxime groups capable of forming homomeric or heteromeric capsules through hydrogen bonding is reported. The final step in each synthesis, the aldehyde to oxime transformation, has been achieved in excellent yields through 'solvent assisted grinding'.

Reactivation of immobilized acetylcholinesterasetabun complex by pralidoxime, its isomers, and homologs

Reactivation efficacy of three homologous and three isomeric series of pralidoxime-type reactivators with aldoxime group in position 2, 3 and 4 of the heterocycle was tested in reactivation of tabun-inhibited AChE. The experiments were performed with immobilized and stabilized porcine brain AChE. The enzyme acticity was measured by Ellman method. Reactivation efficacy was determined by measurement of indicator fabric coloration intensity as a measure of AChE activity. Of the studied group of nine reactivators, isomers with the functional group in position 2 were the most effective. The highest value (30 %) for reactivation of inhibited AChE was found for 2PAE after treatment for 15 min at concentration 0.5 mg/cm3. The efficacy of the isomers decreased in the order ortho > para > meta. No marked effect on the efficacy of the reactivators was observed on prolongation of the reactivation time. The reactivators efficacy decreased with decreasing concentration of their solutions.

Preparation, characterization and reactivity of 1-benzylpyridinium-4-aldoxime chloride and 1-phenacylpyridinium-4-aldoxime chloride and their complexes with the aquapentacyanoferrate(II) ion

Abstract A detailed structural characterization of the biologically active 1-benzylpyridinium-4-aldoxime chloride and 1-phenacylpyridinium-4-aldoxime chloride was performed using NMR and vibrational and electronic spectroscopy, as well as X-ray diffraction. The complexes of these compounds with the aquapentacyanoferrate(II) ion were examined in solution, isolated as solids and characterized by elemental analysis, electronic, FT-IR and NMR spectral data. They were found to be mononuclear substituted pentacyanoferrates(II) containing the aldoxime group coordinated to the iron through the nitrogen atom. The complexes were also precipitated in the form of the respective zinc salts; the analysis of these complexes revealed a molar Fe/Zn ratio of 1, thus confirming the charge of the complex anions to be −2. The ionization constants of the aldoxime group in the free ligands and in the respective cyano complexes were also determined. Despite the presence of two donor sites in 1-phenacylpyridinium-4-aldoxime chloride, only the aldoxime group was found to be reactive.

Efficacy of Eight Experimental Bispyridinium Oximes Against Paraoxon-Induced Mortality: Comparison with the Conventional Oximes Pralidoxime and Obidoxime

Recently, several experimental K-oximes with two functional aldoxime groups have been synthesized that show excellent in vitro efficacy in protecting acetylcholinesterase (AChE) from inhibition by a broad variety of organophosphorus compounds (OPCs). However, oximes themselves are also AChE inhibitors, albeit at higher concentrations, which is a major cause of their toxicity and may be a dose-limiting factor in oxime therapy. To assess the efficacy of the experimental K-oximes in vivo, the extent of oxime-conferred protection from mortality induced by paraoxon was quantified. Rats received paraoxon in a dosage of 1, 5, or 10 mumol, and immediately thereafter intraperitoneal injections of the respective oxime at a dosage of half the LD(01). The relative risk of death (RR) over time was estimated by Cox survival analysis for treatment with experimental K-oximes (K-53, K-74, K-75, K-107, K-108, and K-113), with the clinically available oximes pralidoxime (2-PAM) and obidoxime, and with the well-characterized K-oximes K-27 and K-48, comparing results with the no-treatment group. Best protection was conferred by K-27, reducing the RR to 20% of controls (P </= 0.05), which was significantly (P <or= 0.05) better than all other tested oximes. Marked reduction in mortality was also achieved by K-48 and the three new bispyridinium oximes containing two aldoxime groups, but no xylene linker: K-48 (RR = 0.32), K-53 (RR = 0.36), K-74 (RR = 0.42), K-75 (RR = 0.35). This effect was significantly (P <or= 0.05) superior to that of all other oximes, except K-27. The remaining oximes, i.e., obidoxime (RR = 0.64), 2-PAM (RR = 0.78), K-107 (RR = 0.70), K-108 (RR = 0.77), and K-113 (RR = 0.87) reduced paraoxon-induced mortality only poorly, but significantly (P <or= 0.05). Our data show that K-27, K-48, K-53, K-74, and K-75, due to their far superior in vivo efficacy, are the most promising candidates to eventually replace the established oximes 2-PAM and obidoxime. Further studies in other species exposed to a broader spectrum of OPCs are, however, necessary before considering their use in humans.

P.5.096 The influence of calcium channel blockade on rat picrotoxin-induced hyperkinesis

Our previous attempts to design muscarinic agonists related to arecoline with the prerequisites for clinical use were successful with the discovery of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, RU 35963, and structurally related compounds, in which the metabolically labile ester group of arecoline was replaced with the bioisosteric and stable aldoxime group. With the aim of obtaining compounds with improved cholinomimetic properties, several aryl- and alkyl-carbamates of RU 35963, as well as O-alkyl-, and O-aryl-carbamates of the 1-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, 24, have been synthesized and evaluated biologically. The most interesting molecules to emerge from the primary screening have been evaluated more extensively and their cholinomimetic profiles compared with those of the parent molecules. In vitro studies indicate that none of these prodrugs have affinity for muscarinic receptor sites and some of them (aryl-carbamates) have cholinesterase inhibiting properties. Results from in vivo experiments in mice and rats showed that these new substances, 1-[4-chlorophenyl] oxycarbonyl-1,2,5,6-tetrahydropyridine-3- carboxaldehyde-O-methyloxime (16 = RU 47213) in particular, have cholinomimetic properties that compare favourably with those of the parent compounds. After oral administration 16 was clearly superior to RU 35963 in terms of central selectivity, duration of action and therapeutic indexes.

Structural Bioinformatics and QSAR Analysis Applied to the Acetylcholinesterase and Bispyridinium Aldoximes

The methods of bioinformatics, molecular modelling, and quantitative structure-activity relationships (QSARs) using regression and artificial neural network (ANN) analyses were applied to develop safer aldoxime antidotes against poisoning by organophosphorus (OP) agents with high, mean, and low aging rates. We start here from a molecular modelling of the mouse AChE at an atomistic level. Aim is to predict qualitatively the structural requirements of an aldoxime that shows an unique reactivating activity against the three classes of OPs. An antidotal action should occur by a three-site mechanism: the aldoxime groups of the first pyridinium ring should point towards the catalytic site, and the second pyridinium ring and its substituents should be anchored at the peripherical and anionic subsites. Based on this model, it is predicted that a suitable substituent is based on an arginine-like moiety. Then, an ANN-based QSAR analysis using a training set of aldoximes with known structure and activities was applied. Its input layer consisted of seven nodes: the group-membership descriptors that parameterize the type of the OP, the logarithms of the distribution coefficients at pH 7.4 and their squared term, the lowest unoccupied molecular orbital (LUMO) energies, the scaled molar refractions of the substituents, and their squared term. It was shown that the qualitative prediction made by molecular modelling can be quantified by an ANN prediction.

A Z Isomer of 5-Nitrofuran-2-aldoxime

The molecule of the title compound (C 5 H 4 N 2 O 4 ) is practically planar; the dihedral angles between the ring plane and the planes of the nitro group and the aldoxime group are 5.0(3) and 4.4(3)°, respectively. Intermolecular O4-H4...N2 hydrogen bonds, with O-H = 0.96 (5), H...N = 1.89 (5), N...O = 2.827 (5) A and O-H...N = 164(1)°, connect molecules into infinite chains along the b axis.

Synthese und Charakterisierung von Stilbazoliumfarbstoffen mit mesoionischer 1,2-Diaziniumstruktur

Synthesis and Characterization of Stilbazolium Dyes with Mesoionic 1,2-Diazinium Structure Pyridazinium salts of typ 1 react with substituted aromatic and heteroaromatic aldehydes 2a, e–h, 8a–c and trans-p-dimethylamino-cinnamaldehyde 3a to the charge transfer dyes 4a–h, 5a–d, 9a–c. They absorb in the range between 380 and 660°nm. The dehydratisation of the aldoxime group in 4, 5 to the nitril group under formation of 6, 7a–d causes a bathochromic shift of the absorption band up to 110 nm. The UV-VIS data are discussed dependent on the structure of the dyes.