O-substituted Oximes Research Articles

Characterization of Stable Pyrazole Derivatives of Curcumin with Improved Cytotoxicity on Osteosarcoma Cell Lines.

Curcumin (CUR) is a natural molecule that is unstable due to the presence of a bis-ketone. To obtain more stable derivatives in biological fluids, the bis-ketone was replaced with pyrazole or O-substituted oximes. Their stability in solution was studied by UV-visible spectrophotometry. The effects on proliferation were studied by MTT assay and/or clonogenicity assay. Induction of apoptosis was evaluated by annexin V staining and Western blot analysis. The bioavailability was obtained from the analysis of the molecular chemical-physical characteristics. The replacement of the bis-ketone with a pyrazole ring or O-substituted oximes improved the stability of all the CUR-derivative molecules. These derivatives were more stable than CUR in solution and were generally cytotoxic on a panel of cancer cell lines tested, and they promoted caspase-dependent apoptosis. Derivative 1 was the most potent in the osteosarcoma (OS) lines. With respect to CUR, this derivative showed cytotoxicity at least three times higher in the MTT assay. In addition, in the clonogenic assay, 1 maintained the activity in conditions of long treatment presumably by virtue of its improved stability in biological fluids. Notably, 1 should have improved chemical-physical characteristics of bioavailability with respect to CUR, which should allow for reaching higher blood levels than those observed in the CUR trials. In conclusion, 1 should be considered in future clinical studies on the treatment of OS, either alone or in combination with other medications currently in use.

Polytopal Rearrangement Governing Stereochemistry of Bicyclic Oxime Ether Synthesis.

In the present study, four O-substituted oximes of quinuclidin-3-one were synthesized using appropriate O-substituted hydroxylamine hydrochlorides. In order to perform these reactions in a solvent, a mixture of (E) and (Z) products was yielded. Using mechanochemical and microwave synthesis, we then obtained pure (E) oximes. In almost all cases, the conversion to oxime ethers was completed. Reactions were monitored by ATR spectroscopy and the ratios of (E) and (Z) oxime ethers were deduced from 1H NMR data. Several reactions were very rapid (1 min) with 100% conversion and stereospecificity. To investigate the reaction mechanisms, full conformational analyses of the reaction intermediates were performed and the lowest energy conformers were determined. These conformers differed in spatial arrangement around the nitrogen atom of the amino group and were in the correct orientation for reactions to occur. Calculated standard Gibbs energies of the formation were in agreement with the experimentally obtained ratios of (E) and (Z) isomers. This work shows alternatives to the classical synthesis of O-substituted oxime ether precursors and highlights the fast reaction rate and stereoselectivity of microwave synthesis as well as the “green” aspects of mechanochemistry.

Stereoselective self-aggregation of zinc bacteriochlorophyll-d analogs possessing an O-substituted oxime moiety at the 13-position

Zinc methyl 3-hydroxymethyl-131-deoxo-pyropheophorbides-a possessing a variety of O-substituted oxime moieties at the 13-position were prepared as models of bacteriochlorophyll-d, which could be found in the main light-harvesting system of green photosynthetic bacteria by chemical modification of naturally occurring chlorophyll-a. The E/Z-stereoisomers of the synthetic O-substituted oximes were successfully separated by silica gel column chromatography. Most of these zinc bacteriochlorophyll-d analogs formed J-type self-aggregates in an aqueous Triton X-100 micelle solution, affording large oligomers whose Soret and Qy bands were red-shifted, compared with those of their monomers in tetrahydrofuran. The self-aggregation was dependent on their E/Z-stereochemistry. Thus, the E-stereoisomers showed the red-shifted electronic absorption bands, which were similar to those of the original bacteriochlorophyll-d bearing the 131-oxo group. On the other hand, the Z-stereoisomers exhibited the less red-shifted absorption bands than did the E-stereoisomers, to give different self-aggregates. In addition, the self-aggregation could be controlled by the size of the O-substituents in the oxime moiety.

‘Click Synthesis’ of Some Novel O‐Substituted Oximes Containing 1,2,3‐Triazole‐1,4‐diyl Residues as New Analogs of β‐Adrenoceptor Antagonists

AbstractThe ‘click synthesis’ of some novel O‐substituted oximes, 7a–7t, which contain 1,2,3‐triazolediyl residues, as new analogs of β‐adrenoceptor antagonists is described (Schemes 1–4). The synthesis of these compounds was achieved in four to five steps. The formation of oximes of 9H‐fluoren‐9‐one and benzophenone, i.e., 9a and 9b, respectively, followed by their reaction with propargyl bromide, afforded O‐propargyl oximes 10a and 10b, respectively, which by a subsequent CuI‐catalyzed Huisgen cycloaddition with prepared β‐azido alcohols 11a–11j (Schemes 2 and 3), led to the target compounds 7a–7t in good yields.

Synthesis and antimicrobial activity of some new flavonyl oxime ether derivatives.

The synthesis of a series of 6 compounds related to 2-(4'-formyl-phenyl)-4]H-1-benzopyran-4-one O-substituted oxime and the results of a study of their biological activity are reported. The structural assignments of the compounds is based upon various spectral data. The prepared compounds were screened for their in vitro antibacterial and antifungal activities. Compound F3 exhibited the best antifungal activity compared with ketoconazole and fluconazole.

ChemInform Abstract: Some Properties of Cyclopropenone Oximes Under Beckmann Reaction Conditions.

The reaction of diphenylcyclopropenone oxime (1a) with acetyl or tosyl isocyanate, carboxylic anhydrides, or nitrohalobenzenes yielded the cyclopropenone O-substituted oxime derivatives. Treating with thionyl bromide and chloride 1a gave 3-haloacrylonitriles. Whereas 1a as well as other cyclopropenone oximes, were stable under acidic conditions, heating in methanolic sodium hydroxide gave the ring-opened α,α-dimethoxyketones oximes.

ChemInform Abstract: Synthesis and Antimicrobial Activity of Some New Flavonyl Oxime Ether Derivatives.

The synthesis of a series of 6 compounds related to 2-(4’-formyl-phenyl)-4H-1-benzopyran-4- one O-substituted oxime and the results of a study of their biological activity are reported. The structural assignments of the compounds is based upon various spectral data. The prepared compounds were screened for their in vitro antibacterial and antifungal activities. Compound F3 exhibited the best antifungal activity compared with ketoconazole and fluconazole.

Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives

In an attempt to find novel azole antifungal agents with improved activity and broader spectrum, computer modeling was used to design a series of new azoles with piperidin-4-one O-substituted oxime side chains. Molecular docking studies revealed that they formed hydrophobic and hydrogen-bonding interactions with lanosterol 14α-demethylase of Candida albicans (CACYP51). In vitro antifungal assay indicates that most of the synthesized compounds showed good activity against tested fungal pathogens. In comparison with fluconazole, itraconazole and voriconazole, several compounds (such as 10c, 10e, and 10i) show more potent antifungal activity and broader spectrum, suggesting that they are promising leads for the development of novel antifungal agents.

Synthesis of Quinolines and 2H‐Dihydropyrroles by Nucleophilic Substitution at the Nitrogen Atom of Oxime Derivatives

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Quinolines and 2H-Dihydropyrroles by Nucleophilic Substitution at the Nitrogen Atom of Oxime Derivatives

Isomerization of oxime derivatives was researched in detail to find out the methods for the syn-anti isomerization of O-substituted oximes. Based on these findings were developed simple methods for the preparation of aza-heterocycles from both stereoisomers of oximes. Quinolines were synthesized from β-aryl ketone oximes by treatment with trifluoroacetic anhydride and 4-chloranil. γ,δ-Unsaturated O-methoxyacetyloximes were transformed to 2H-dihydropyrroles by reaction with methoxy-acetic acid.

Synthesis and muscarinic activity of 1,2,3,4-tetrahydropyrimidine derivatives.

3-Methyl-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde O-substituted oximes 4 and 1-(3-methyl-1,2,3,4-tetrahydropyrimidin-5-yl)ethanone O-substituted oximes 9 have been prepared as bioisosteric congeners of arecoline which is a muscarinic agonist for treatment of Alzheimer's disease. Starting from pyrimidine-5-carbaldehyde 1, formation of the 3-methylpyrimidinium salt and subsequent reduction afforded 1,2,3,4-tetrahydropyrimidine derivatives which were converted into oxalate salts in the interest of purity and stability. Binding affinities of prepared compounds for the cloned human muscarinic M1 receptor (h-M1) were determined by radioligand binding assay using [3H]-N-methylscopolamine (NMS).

Stereomutation of the Enantiomers of HinderedO-Substituted Oximes

As anticipated by Molecular Mechanics calculations, the (E) and (Z) isomers of diaryl ketone oximes containing a bulky substituent (PhS or Ph2N) in the ortho position of the phenyl ring, display different conformational preferences. Whereas the (E) isomers exhibit a plane of symmetry at any accessible temperature, the (Z) isomers exist as a pair of stereolabile enantiomers that were detected by low-temperature NMR spectroscopy in a chiral environment. In a number of O-substituted oximes, the enantiomerisation barriers of the (Z) isomers were determined by monitoring the line shape of the NMR signals of diastereotopic methylene hydrogen atoms as a function of temperature. The four stereoisomers, generated by the combination of the conformational axial chirality with the configurationally stable chirality of a stereogenic centre, have been all detected in a specifically substituted oxime and monitored in an appropriate chiral environment. The NMR results in solution were confirmed by X-ray diffraction measurements in the solid state.

O-(2,3,4,5,6-Pentafluorobenzyl)oxime-trimethylsilyl ester derivatives for sensitive identification and quantitation of aldehydes, ketones, and oxoacids in biological fluids

The importance of oxoacids in clinical medicine and the analytical difficulties involved in exact quantitation of low concentrations in physiological fluids (decarboxylation, dimerization and enolization) have resulted in continuing efforts to find the best suited derivative for stabilization of the oxogroup prior to gas chromatography. We have found the gas chromatographic properties of aldehydes, ketones and oxoacids in the form of their O-(2,3,4,5,6-pentafluorobenzyl)oxime-trimethylsilyl esters (0-PFBoxime-TMS esters) advantageous to the commonly used 0-ethoxime-TMS esters [l]. The formation of double peaks, corresponding to the syn and anti isomers, is less pronounced, and the higher molecular mass shift on derivatization permits the detection and quantitation of aldehydes and ketones in addition to oxoacids, compounds which elute in the solvent front with other O-substituted oxime derivatives and are therefore not detectable. We describe here some special features of the EI mass spectra of 0-PFBoxime-TMS esters providing a further increase in sensitivity and specificity.

Some Properties of Cyclopropenone Oximes under Beckmann Reaction Conditions

Abstract The reaction of diphenylcyclopropenone oxime (1a) with acetyl or tosyl isocyanate, carboxylic anhydrides, or nitrohalobenzenes yielded the cyclopropenone O-substituted oxime derivatives. Treating with thionyl bromide and chloride 1a gave 3-haloacrylonitriles. Whereas 1a as well as other cyclopropenone oximes, were stable under acidic conditions, heating in methanolic sodium hydroxide gave the ring-opened α,α-dimethoxyketones oximes.

1-Alkoxyamino-1-deoxy alditols, useful u.v.-absorbing derivatives of neutral and acidic oligosaccharides

The feasibility of using 1-alkoxyamino-1-deoxy alditol derivatives to facilitate the purification and structural characterization of oligosaccharides was examined. 1-Benzyloxyamino-1-deoxy, 1-deoxy-1- p-nitrobenzyloxyamino, and 1-deoxy-1-[4-( p-nitrophenyl)butoxyamino] alditol derivatives of mono- and oligo-saccharides were prepared by reduction of the corresponding O-substituted oximes with sodium cyanoborohydride. The 1-alkoxyamino-1-deoxy alditol derivatives were separated by h.p.l.c. and characterized by 1H-n.m.r. spectroscopy and f.a.b.-m.s. Per- O-methylation of the 1-benzyloxyamino-1-deoxy and 1-deoxy-1- p-nitrobenzyloxyamino alditol derivatives resulted in the elimination of a benzaldehyde moiety and formation of a quaternary ammonium salt. The positive mode f.a.b. mass spectra of these cationic per- O-methylated derivatives of oligosaccharides included very intense molecular ion signals, suggesting the possibility of a significant reduction in the amount of per- O-methylated oligosaccharide required for f.a.b.-m.s. analysis. Because the ionic nature of the derivatives hinders their analysis by g.c.-m.s. a new reagent, 4-( p-nitrophenyl)butoxyamine, was synthesized and used to prepare the 1-deoxy-1-[4-( p-nitrophenyl)butoxyamino] alditol derivatives of several mono- and oligo-saccharides. These could be separated by h.p.l.c., with detection by u.v. absorption, and they were stable under O-methylation conditions. The per- O-methylated derivatives of oligosaccharides can be analyzed by e.i.-m.s. as well as f.a.b.-m.s. O-Methylated 1-deoxy-1-[4-( p-nitrophenyl)butoxyamino] alditol derivatives of monosaccharides are amenable to processing by g.c.—m.s., allowing standard methylation analysis of derivatized oligosaccharides to be performed. Thus, the separation and structural analysis of oligosaccharides are facilitated by the physical and chemical properties (u.v. absorption, ease of separation by h.p.l.c., stability to methylation and hydrolysis conditions, and ease of analysis by g.c.—m.s. and f.a.b.-m.s.) imparted to oligosaccharides by forming the 1-deoxy-1-[4-( p-nitrophenyl)butoxyamino] alditol derivatives.

Geometrical isomerism of the o-substituted oximes of some keto-steroids

O-Benzyl- and/or O-iso-propyl-oximes of a number of 3-, 7- or 20-oxo-steroids and of some 3,20-di-oxosteroids have been prepared. The products were characterized by their C,H,N-content and physical properties and studied by UV, 1H- and 13C-NMR spectroscopy. The ketoximes of 3-oxo-Δ 4-steroids were invariably found to consist of a mixture of two geometrical isomers, denominated syn and anti. In some cases both isomers could be obtained in a pure state by column-chromatography. Oximes of the 7-oxo-Δ 5-steroids were found to consist only of the syn isomer, whereas the 20-oximino compounds showed no isomerism.

Exchange of oxime functions: A useful reaction in GC-MS analysis of steroids

Simple and various O-substituted oxime derivatives of steroids may be interconverted by an acid-catalyzed reaction of the oxime with the appropriate substituted hydroxylamine hydrochloride in pyridine. For example, unsubstituted oximes of common hormonal steroids with keto groups in positions 3, 17, and 20 are converted into O-methyloximes by reaction of the oximes with 5 mg of methoxyamine hydrochloride in 50 μl of pyridine for 1 hr at 100°C. The reaction involves cleavage of the carbon-nitrogen bond and follows pseudo-first-order kinetics in the presence of excess reagent. The conversion of an oxime with a small O-substituent into one with a larger O-substituent was faster than the reverse reaction at the C-3 position. The rate of conversion depends on the position of the oxime function and decreases in the order: C-3 > C-20 > C-17 > C-11. The proximity and the configuration of other functional groups also influence the rates. Thus, determination of reaction rates with the aid of gas chromatography-mass spectrometry may be used to determine the positions of functional groups in steroids. The reactions are likely to be applieable to other groups of compounds possessing keto or aldehyde functions.

Asymmetric syntheses. Part IX. Reduction of ketone oximes and their O-substituted derivatives with the lithium aluminium hydride–3-O-benzyl-1,2-O-cyclohexylidene-α-D-glucofuranose complex to give optically active amines

The asymmetric reduction of ketone oximes and their O-tetrahydropyranyl and O-methyl derivatives with the lithium aluminium hydride–3-O-benzyl-1,2-O-cyclohexylidene-α-D-glucofuranose complex yields optically active amines of up to 56% optical purity. The stereoselectivities obtained from reduction of the O-substituted oximes were similar to those from the reduction of the free oximes. All the resulting amines have the S-configuration and this method may be used in determining the absolute configurations of amines. Asymmetric reduction with the ethanol-modified glucofuranose complex gives optically active amines of the R-configuration.