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At least 811 records · Page 45Linked to original sources
PubMed1994

New NO-donors with antithrombotic and vasodilating activities, IV: Chemical reactivity of nitrosimines and its implications for their pharmacologic properties.

Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the = N-NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37 degrees C. Only at higher temp. (70 degrees C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO. and N2O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N2O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO. was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NO- plays an important role in the stimulation of s-GC.

Fibrinolytic Agents↗
PubMed2004

Regioselectivity in iron-catalyzed [2+2+1] cycloadditions: a DFT investigation of substituent effects in 1,4-diazabutadienes.

The transition-metal-catalyzed [2+2+1] cycloaddition reaction of 1,4-diazabutadienes, in which the imine-carbon atoms are part of an oxazine ring system, with ethylene and carbon monoxide leads to the regioselective formation of pyrrolidinone derivatives. To explain this regioselectivity, the transition states and intermediates of the rate-determining step of the catalysis are determined by high-level DFT calculations. The experimentally observed regioselectivity is consistent with the lower activation energy of the addition of ethylene towards the carbon atom next to the oxazine oxygen atom. Furthermore, the activation barrier of a conceivable back reaction is higher for the intermediates with the experimentally observed regioselectivity. These thermodynamic and kinetic arguments at first sight appear to be confirmed by the calculated NPA charges in the transition states, which reveal that the differences in these charges are greatest for those transition states that lead to the formation of the energetically favored transition structures. Nevertheless, calculations of analogous transition structures and reaction products starting from 1,4-diazabutadienes with a 2-fluoro, 2-hydroxo or 2-amino substituent revealed that the regioselectivity is not determined by the electronegativity of the heteroatom and thus by the differences in the NPA charges or the resulting Coulombic interactions in the transition structures. The main reason for the observed regioselectivities is the pi-donor ability of the substituent to contribute to a delocalized pi system incorporating the adjacent imine moiety. The increasing pi-donor capability results in decreased reactivity of this moiety and increases the (relative) reactivity of the second imine group. This effect can even overcompensate for strong intramolecular Coulombic attractions in the transition structures.

Journal Article↗
PubMed2005

Novel multichiral diols and diamines by highly stereoselective pinacol coupling of planar chiral [2.2]paracyclophane derivatives.

The TiCl4/Zn-mediated intermolecular pinacol coupling of the planar chiral carbonyl compounds [2.2]paracyclophane-4-carbaldehyde, 4-acetyl[2.2]paracyclophane (ketone) and the four regioisomeric 5-, 7-, 12- and 13-methoxy[2.2]paracyclophane-4-carbaldehydes as well as the pTosOH-Zn/Cu-promoted coupling of their N-substituted imines is described. Coupling of the enantiomerically pure substrates (most of carbonyl compounds and all imines) occurs stereoselectively giving rise to diastereomerically pure 1,2-diols and 1,2-diamines. Racemic aldehydes and ketone react with different degrees of stereoselectivity (depending on the substituents in certain positions) and produce one to three diastereomers. 7-methoxy[2.2]paracyclophane-4-carbaldehyde undergoes a tandem pinacol coupling-pinacol rearrangement to yield bis-(7-methoxy[2.2]paracyclophane-4-yl)acetaldehyde. Coupling of the racemic imines produces a mixture of single racemic D,L-diamine and single meso-diamine in each case. The stereoselective formation of the asymmetric centres is governed by the planar chiral [2.2]paracyclophanyl moiety. The techniques elaborated are extended to the intramolecular coupling of [2.2]paracyclophane-4,13-dicarbaldehyde and its bis-N-phenylimine, resulting in stereoselective formation of the chiral triply-bridged diol and exclusive formation of the meso-diamine. X-Ray investigations of several diols and diamines have been carried out and the structural features of these derivatives are discussed.

Journal Article↗
PubMed2005

Bifunctional-thiourea-catalyzed diastereo- and enantioselective aza-Henry reaction.

Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-beta-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N-Boc-imines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.

Catalysis↗
PubMed2006

Helicate, macrocycle, or catenate: Dynamic topological control over subcomponent self-assembly.

The aqueous reaction between equimolar amounts of 2-(2-(2-aminoethoxy)ethoxy)ethanamine, 1,10-phenanthroline-2,9-dialdehyde and copper(I) produced a dimeric helical macrocycle in quantitative yield. This ring could also be generated by the addition of two equivalents of the diamine to an acyclic helicate containing four mono-imine residues: A transimination occurred, the chelate effect being implicated as a driving force. In the case of a helicate containing mono-imines derived from anilines, the substitution of diamine for monoamine was reversible upon lowering the pH. The aliphatic diamine was protonated at a higher pH than the arylamine, which left the arylamine free for incorporation instead of the alkyl diamine. This reaction thus opened the possibility of switching between closed macrocyclic and open helicate topologies by changing the pH. An additional closed topology became accessible through the use of a diamine that incorporates two rigid phenylene spacer groups between a flexible chain and the imine-forming nitrogen atoms. The resulting catenate consists of a pair of topologically interlinked macrocycles. The presence of the phenylene groups appeared to dictate the topology of the final product, making the formation of a single macrocycle energetically disfavoured.

Journal Article↗
PubMed2006

A dynamic tricopper double helicate.

The reaction between 8-aminoquinoline, 1,10-phenantholine-2,9-dicarbaldehyde, and copper(I) tetrafluoroborate gave a quantitative yield of a tricopper double helicate. The presence of dynamic covalent imine (C=N) bonds allowed this assembly to participate in two reactions not previously known in helicate chemistry: 1) It could be prepared through subcomponent substitution from a dicopper double helicate that contained aniline residues. An electron-poor aniline was quantitatively displaced; a more electron-rich aniline competed effectively with the aminoquinoline, setting up an equilibrium between dicopper and tricopper helicates that could be displaced towards the tricopper through the addition of further copper(I). 2) Both dicopper and tricopper helicates could be prepared simultaneously from a mixture of phenanthroline dialdehyde, aniline, and aminoquinoline, which contained all possible imine condensation products in equilibrium. Following the addition of copper(I), thermodynamic equilibration on both covalent and coordinative levels eliminated all partially-formed and mixed imine ligands from the mixture, leaving the helicates as exclusive products.

Journal Article↗
PubMed2002

Hyaluronate-heparin conjugate gels for the delivery of basic fibroblast growth factor (FGF-2).

The stability and activity of recombinant growth factors administered locally for the repair of damaged tissue can be directly influenced by the physical structure and chemical composition of the delivery matrix. This study describes a novel basic fibroblast growth factor-2 (FGF-2) delivery system synthesized by the conjugation of a structure-stabilizing polymer, hyaluronate (HA), with a sulfated glycosaminoglycan, heparin (HP), that has inherent specific binding sites for members of the FGF family. The biopolymers were formed via stable amine or labile imine bonds by coupling amine-modified HA with oxidized heparin. The addition of recombinant human FGF-2 resulted in the rapid binding of FGF-2 to the heparin segment of the hyaluronate-heparin (HAHP) conjugate. The FGF-2 was released in vitro from the imine-bonded (HAHPi) gels in the form of FGF-2-heparin complexes through the hydrolysis of the imine bonds. In contrast, the release of growth factor from the more stable amine-bonded (HAHPa) gels required treatment with free heparin or enzymatic digestion of the hyaluronate segment. Functional analysis of the released FGF-2 showed that the HAHP conjugate gels increased both the stability and activity of the growth factor.

3T3 Cells↗
PubMed1985

Two distinct mechanisms for the interaction of cells with fibronectin substrata.

Fibronectin (Fn) was adsorbed onto neutral, sulfonated, imine-conjugated or gelatin coated polystyrene latex beads. In all cases, the Fn coated beads bound effectively to Chinese hamster ovary (CHO) cells in suspension. However, the binding of Fn coated neutral or positively charged imine conjugated bead was inhibited by low concentrations of heparin or heparan sulfate or by treatment of the cells with Flavobacterium heparanase. By contrast, binding of Fn coated sulfonated or gelatin beads was insensitive to inhibition by heparin and to heparanase treatment of cells. Adhesion of CHO cells to Fn coated tissue culture plastic was not sensitive to heparin, whereas adhesion of CHO cells to Fn-coated imine-conjugated plastic was sensitive to heparin. These observations imply that the functional status of Fn can be modulated by the nature of the surface to which the Fn is adsorbed. They further imply that, under some circumstances, the heparin/heparan sulfate binding domains of Fn can play a role in the attachment of Fn to the cell membrane via membrane proteoglycans. Under other circumstances, the interaction of Fn with the cell may primarily involve other receptors for Fn, presumably cell surface glycoproteins.

Animals↗
PubMed2000

Acetochlor-induced rat nasal tumors: further studies on the mode of action and relevance to humans.

The herbicide acetochlor, and its analogue alachlor, have similar toxicological properties, the most significant being the induction of nasal adenomas in rats in 2-year feeding studies. Previous investigations have proposed a mode of action involving metabolism to a quinone-imine, the formation of protein adducts, cell death, and compensatory hyperplasia leading to the observed adenomas. Comparisons between rats and humans of the metabolic cascade leading to the quinone-imine indicate that these chemicals do not pose a threat to humans. Further investigations with acetochlor, presented here, have revealed an additional activation pathway in which a sulfoxide metabolite of acetochlor plays a key role. The sulfoxide was found to be the major plasma metabolite in rats dosed with acetochlor. Whole-body autoradiography studies established that this metabolite selectively accumulates and persists in the olfactory epithelium of rats. Radiolabeling of the sulfoxide molecule in the phenyl ring and in the sulfoxide side-chain demonstrated that the metabolite accumulating in nasal tissues retains the sulfoxide side-chain. The formation of a quinone-imine from the sulfoxide was facilitated by hydroxylation of the phenyl ring by a cytochrome P450 isoenzyme which was specific to the nasal epithelium in the rat. This metabolic conversion could not be detected in 33 fresh human nasal tissue samples, supporting the earlier view that the acetochlor-induced rat nasal tumors do not represent a hazard for humans.

Adenoma↗
PubMed2001

Analgesic and toxic effects of neonicotinoid insecticides in mice.

Several nicotinic agonists with the 6-chloro-3-pyridinyl moiety are potent insecticides (e.g., the neonicotinoids imidacloprid and thiacloprid) while others are candidate nonopioid and nonantiinflammatory analgesics (i.e., epibatidine and several heterocyclic analogs). This study examines the hypothesis for the first time that the neonicotinoid insecticides and their imine metabolites and analogs display analgesic (antinociceptive) activity or adverse toxic effects associated with their action on binding to the alpha 4 beta 2 nicotinic acetylcholine receptor (AChR) subtype. Seven 6-chloro-3-pyridinyl compounds were studied, i.e., imidacloprid and thiacloprid, the corresponding imines and an olefin derivative, a nitromethylene analog, and (+/-)-epibatidine. Like (-)-nicotine and carbachol, they all act as full agonists in the (86)rubidium ion efflux experiment with intact mouse fibroblast M10 cells stably expressing the alpha 4 beta 2 nicotinic AChR. Their agonist action is correlated with binding affinity to the alpha 4 beta 2 receptor from M10 cells. Imidacloprid, thiacloprid, and their imine analogs are not antinociceptive agents in mice by abdominal constriction and hot plate analgesic tests. Their agonist actions at the alpha 4 beta 2 receptor correlate instead with their toxicity. Surprisingly, the nitromethylene analog, a weak agonist, is as potent as (-)-nicotine in inducing antinociception, and the effect persists longer than that caused by (-)-nicotine. However, mecamylamine (1 mg/kg) prevents antinociception induced by (-)-nicotine but not by the nitromethylene analog. Interestingly, this nitromethylene neonicotinoid insecticide gives 80-100% mortality within 15 min at 3 mg/kg with mecamylamine pretreatment at 2 mg/kg, doses at which each agent alone gives no lethality. Therefore, analgesic and toxic effects of the nitromethylene analog differ in their mechanism of action from (-)-nicotine and (+/-)-epibatidine.

Analgesics, Non-Narcotic↗
PubMed2003

Molecular modeling of penicilloate anions: an RHF-SCF analysis.

An ab initio restricted Hartree-Fock self-consistent field (RHF-SCF) analysis of penicilloate anions was performed at the TZV level with GAMESS. Geometry optimization was initialized by the semi-empirical AM1 method followed by optimization at the 6-31++G** level. The total energy obtained was -1116.0997 a.u. for the penicilloate amine, -1115.3164 a.u. for the imine, -1115.2969 a.u. for the enamine and -1115.2017 a.u. for the amine that was deprotonated at the thiazolidine nitrogen. Formation of the free thiolate in the imine and enamine anions by deprotonation of the penicilloate amine is associated with: (1) an increase in total energy (2) an increase in the energy of the highest occupied molecular orbital (HOMO) to that of anti-bonding (3) a decrease in chemical hardness (4) an increase in the chemical potential (5) a more negative Mulliken net charge on the sulfur atom and (6) an increase in the Mulliken atomic population on the former thiazolidine sulfur atom in the HOMO. The RHF-SCF analysis presented here suggests a potential role for the thiolate sulfur of penicilloate anions, especially of the imine, as a chemically reactive soft nucleophile.

Allergens↗
PubMed2005

Recent advances in 1,3-dipolar cycloaddition reactions on solid supports.

Solid-phase methods are of a great significance in organic synthesis. Recent developments of these methods are providing new ways to construct libraries of small organic molecules. Five-membered heterocyclic compounds, which can be utilized in a variety of applications, are formed in the 1,3-dipolar cycloaddition reaction between dipolarophiles and dipoles. This review deals with the solid-phase synthesis of heterocycles via [3+2] cycloaddition reaction. Cycloaddition reactions of polymer-bound dipoles and polymer-bound dipolarophiles and intramolecular solid-phase cycloadditions are discussed in separate sections. Reactions of dipolarophiles such as alkenes, alkynes, and imines with dipoles such as azomethine ylides, azomethine imines, nitrile imines, azides, nitrones, and nitrile oxides are described. The recent literature up to December 2003 is covered.

Chemistry, Organic↗
PubMed1989

Bioactivation mechanism of L-thiomorpholine-3-carboxylic acid.

L-Thiomorpholine-3-carboxylic acid (L-TMC) is a cyclized analog of S-(2-chloroethyl)-L-cysteine, which is cytotoxic in vitro and nephrotoxic in vivo. To determine whether L-TMC may play a role in S-(2-chloroethyl)-L-cysteine-induced toxicity, the cytotoxicity of L-TMC was studied in isolated rat kidney cells. L-TMC produced time- and concentration-dependent cytotoxicity. Probenecid, an inhibitor of the renal anion transport system, and L-alpha-hydroxyisocaproic acid, a substrate for L-amino acid oxidase, inhibited L-TMC-induced cytotoxicity. Rat kidney cytosol catalyzed the metabolism of L-TMC to a product absorbing at 300 nm. The increase in absorbance at 300 nm was accompanied by an increase in oxygen consumption and was inhibited by L-alpha-hydroxyisocaproic acid; moreover, the absorbance of the metabolite was quenched by addition of potassium cyanide or sodium borohydride, which indicated the formation of an imine. When L-TMC was incubated with rat kidney cytosol and sodium borodeuteride was added at the end of the incubation period, analysis by gas chromatography/mass spectrometry of the tert-butyldimethylsilyl ester of L-TMC showed the formation of [2H]TMC, indicating the intermediate formation of the imine 5,6-dihydro-2H-1,4-thiazine-3-carboxylic acid; chemically synthesized TMC imine showed similar behavior. The enzyme responsible for the metabolism of L-TMC was purified from rat kidney and was identified as L-amino acid oxidase. These observations indicate a role for L-amino acid oxidase in the bioactivation and cytotoxicity of L-TMC.

Amino Acid Oxidoreductases↗
PubMed1988

Drug-protein conjugates--XIV. Mechanisms of formation of protein-arylating intermediates from amodiaquine, a myelotoxin and hepatotoxin in man.

The enzymic and non-enzymic formation of protein-arylating intermediates from amodiaquine (AQ,7-chloro-4-(3'-diethylamino-4'-hydroxyanilino) quinoline), an anti-malarial associated with agranulocytosis and liver damage in man, was studied in vitro. [14C]AQ in phosphate buffer, pH 7.4, under air was autoxidized to a reactive derivative(s) which possessed characteristics indicative of a semiquinone/quinone imine: reduction by NADPH and ascorbic acid, conjugation with thiols and irreversible binding to microsomal and soluble proteins. Cysteinyl SH groups were major sites of arylation. Radiolabelled material irreversibly bound to HSA after 24 hr and to human liver microsomes after 4 hr represented 26.5 +/- 1.8% and 31.4 +/- 0.6% (means +/- SD, N = 3) of incubated [14C]AQ (10 microM), respectively. The quinone imine of AQ(AQQI) was synthesized, and displayed the same oxidative and electrophilic reactions as the product(s) of AQ's autoxidation. A water-soluble product formed in buffered solutions of AQ and N-acetylcysteine was identified as an AQ mercapturate by comparison with an adduct prepared from synthetic AQQI. Irreversible binding of [14C]AQ was inhibited by a radical scavenger; this indicated that the semiquinone imine contributed to the binding. Although AQ was extensively de-ethylated by human liver microsomes, oxidation by cytochrome P-450 did not appear to be principally responsible for its activation and irreversible binding in microsomal incubations. AQ was oxidized to protein-arylating intermediates by horseradish peroxidase. It also formed reactive derivatives, possibly N-chloro compounds, in chlorine solutions. These findings indicated that AQ can give rise to chemically reactive species by at least three distinct mechanisms, viz. autoxidation in neutral solution under air, peroxidase-catalyzed oxidation and N-chlorination. Formation of such species in liver and myeloid cells might be responsible for the adverse reactions associated with AQ.

Adolescent↗
PubMed1986

Porosity-geometry interaction in the conservation of bone strength.

Automated image analysis of a small sample of femoral cross-section radiographs has revealed a consistent difference in bone porosity relative to geometry. Two sub-periosteal fields were assessed microscopically, with field location determined with reference to the principal moment axes (Imax, Imin). The data indicate that: (1) porosity is greatest in the direction of maximum geometric resistance to bending, along the Imin axis; and (2) porosity differences between the Imax and Imin fields decrease as the bone becomes more circular in cross-sectional shape.

Adult↗
PubMed1991

Isolation of a mercapturate adduct produced subsequent to glutathione conjugation of bioactivated 3-methylindole.

Bioactivation of the pneumotoxin 3-methylindole (3MI) to a methylene imine intermediate has been demonstrated previously by trapping the electrophile with glutathione in goat lung microsomal incubations. To determine whether the same bioactivation process occurs in whole animals, 3MI was administered to goats, mice, and rats, and the urinary metabolites from these three species were analyzed by HPLC for the presence of the mercapturate that would be expected as the processed and excreted form of the 3MI-glutathione adduct. The mercapturate, 3-[(N-acetylcysteine-S-yl)-methyl]indole (3MI-NAC), was identified in the urine from all three species and was isolated from rat urine for structural identification by uv, NMR, and mass spectrometry. Synthetic 3MI-NAC had uv, NMR, and chromatographic characteristics identical to the isolated metabolite. The presence of this mercapturate in the urine of treated animals unequivocally demonstrates that 3MI is bioactivated to the methylene imine in vivo and that the glutathione adduct is also formed, presumably to detoxify the methylene imine.

Acetylcysteine↗
PubMed1985

A pulse radiolysis investigation of the oxidation of the melanin precursors 3,4-dihydroxyphenylalanine (dopa) and the cysteinyldopas.

The unstable quinones of 3,4-dihydroxyphenylalanine (dopa) and the most abundant cysteinyldopa isomers (2S-, 5S- and 2,5S,S'-) have been generated rapidly via disproportionation of their respective semiquinones prepared pulse radiolytically by one-electron oxidation of the corresponding dopas with azide radicals. Dopaquinone decays via a base-catalysed unimolecular cyclisation yielding leucodopachrome which, under the present conditions, is immediately oxidised by remaining dopaquinone to form dopachrome and dopa back again. Addition of cysteine increased the rate of dopaquinone decay and precluded dopachrome formation. By contrast, the cysteinyldopa quinones decayed via an acid-catalysed unimolecular cyclisation involving the cysteine side chain to form a cyclic quinone-imine observed directly for the first time. These quinone-imine intermediates subsequently rearranged to more stable phenolic benzothiazine isomers. The addition of cysteine had little effect on cysteinyldopa quinone decay and did not prevent quinone-imine formation. The absorption spectra, extinction coefficients and rate constants for formation and decay of these various transient species involved in melanisation are reported.

Cyclization↗
PubMed2004

Effects of motor imagery on finger force responses to transcranial magnetic stimulation.

The purpose of this study was to investigate whether characteristics of finger interaction seen in voluntary finger force production tasks could also be observed during motor imagery. Transcranial magnetic stimulation (TMS) was applied over the contralateral M1 hand area. Three conditions were tested in eight young healthy volunteers: At rest, during motor imagery of maximal force production by the index finger (ImIn), and during motor imagery of maximal force production by all four fingers simultaneously (ImAll). We obtained measures of motor threshold (MT), motor-evoked potentials (MEP) from the contralateral flexor digitorium superficialis, and TMS-induced forces from individual fingers. Increased MEP and decreased MT during motor imagery tasks suggested enhanced excitability of structures involved in the generation of TMS-induced responses. TMS-induced forces were larger during motor imagery tasks than at rest. This effect was present, albeit significantly smaller, in the middle, ring, and little fingers during ImIn as compared to ImAll. This finding has been interpreted as a correlate of the phenomenon of unintended finger force production (enslaving). The motor imagery effect on finger forces evoked by TMS was significantly larger during ImIn (4% MVC) than during ImAll (2.8% MVC) tasks, corresponding to the phenomenon of force deficit. These results provide direct evidence of the neural origin of the main phenomena of finger interaction. Furthermore, the similarities between characteristics of finger interaction during motor imagery and during voluntary movement suggest the involvement of similar neural structures (including M1).

Adult↗