Ringschlußreaktionen mit N-(Chlormethyl)carbimidoylchloriden, 1. Mitt. Synthesen von Dihydro-1,3,5-triazin-derivaten

Heterocyclisation Reactions with N-(Chloromethyl)carboximidoyl Chlorides, I: Syntheses of Dihydro-1,3,5-triazines N-(Chloromethyl)benzimidoyl chloride ( 1 ) reacts with benzamidine, 2-aminopyridine or 2-aminobenzothiazole to yield the dihydro-1,3,5-triazine derivatives 2 , 3 and 4 whose ¹³C-NMR spectra were used to determine the structures.     

Nitroketenaminale, 11. Mitt.: Zur Umsetzung von Enonen mit N,N′-cyclisch alkylierten Nitroketenaminalen

Nitroketeneaminals, XI: Reaction of Enones with N,N′-Cyclically Alkylated Nitroketeneaminals Reaction of enones 2a - d with nitroketeneaminals 3 , 4 , and 5 in refluxing ethanol yields the Michael adduct 8a and the bicyclic carbinolamines 9, 10 , and 11 . Dehydratisation of 9a - d in acidic medium leads to heteroanellated 1,4-dihydropyridines 12a-d . By means of ¹H-NMR-data the relative configuration of 10d is determined.     

N‐heterocyclic carbenes as ligands in palladium‐mediated [11C]radiolabelling of [11C]amides for positron emission tomography

A model palladium‐mediated carbonylation reaction synthesizing N‐benzylbenzamide from iodobenzene and benzylamine was used to investigate the potential of four N‐heterocyclic carbenes (N,N′‐bis(diisopropylphenyl)‐4,5‐dihydroimidazolinium chloride ( I ), N,N′‐bis(1‐mesityl)‐4,5‐dihydroimidazolinium chloride ( II ), N,N′‐bis(1‐mesityl)imidazolium chloride ( III ) and N,N′‐bis(1‐adamantyl)imidazolium chloride ( IV )) to act as supporting ligands in combination with Pd₂(dba)₃. Their activities were compared with other Pd‐diphosphine complexes after reaction times of 10 and 120 min. Pd₂(dba)₃ and III were the best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [¹¹C]N‐benzylbenzamide in good radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically unreactive and insoluble [¹¹C]CO which was then released and reacted via the Pd‐mediated carbonylation process. Potentially useful side products [¹¹C]N,N′‐dibenzylurea and [¹¹C]benzoic acid were also observed. Increased amounts of [¹¹C]N,N′‐dibenzylurea were yielded when PdCl₂ was the Pd precursor. Reduced yields of [¹¹C]benzoic acid and therefore improved RCP were seen for III /Pd₂(dba)₃ over commonly used dppp/Pd₂(dba)₃ making it more favourable in this case. Copyright © 2010 John Wiley & Sons, Ltd.     

Chemical and Electrochemical Synthesis of Some Substituted N,N′-Diacyl-p-phenylenediamines

Some N,N′-diacyl-p-phenylenediamines substituted with halogens ( 2a - c ) were prepared. Their polarographic reduction in N,N-dimethylformamide with Et₄NClO₄ was performed and discussed. The mechanism of the electrochemical reduction is stated. Large-scale electrolytic reductions of 2a - b to 3a - b were performed.     

Synthesis,radio‐LC–MS analysis and biodistribution in mice of 99mTc–NIM–BAT

S,S′‐bis‐trityl‐N‐BOC‐1,2‐ethylenedicysteamine (S,S′‐bis‐trityl‐N‐BOC–BAT) was conjugated to 2‐nitroimidazole (NIM) through a propylene spacer in order to provide a precursor for a potential technetium‐99 m labelled hypoxia tracer. For labelling with technetium‐99 m, a two‐step one‐pot procedure was developed consisting of deprotection of the ligand by heating in mild acidic conditions and subsequent exchange labelling in the presence of SnCl₂, tartrate and ^99mTcO. The labelling reaction mixture was analyzed using electrospray radio‐LC–MS and the observed mass spectrum corresponding to the main radiometric peak was in accordance with the predicted structure of oxo–Tc(V)–NIM–BAT. ^99mTc–NIM–BAT was purified using RP–HPLC and its biodistribution was evaluated in normal mice at 10 min and 4 h p.i. ^99mTc–NIM–BAT was cleared from plasma mainly by hepatobiliary excretion. Copyright © 2003 John Wiley & Sons, Ltd.     

Antimykotische Wirkstoffe, 10. Mitt. N′-Substituierte N-(1-Adamantyl)harnstoffe

Antimycotic Agents, X: N′-Substituted N-(1-Adamantyl)ureas By nucleophilic addition of 1-aminoadamantane (1) to isocyanates 2 the N′-substituted N-(1-adamantyl)ureas 3 are obtainable. Amenable to this reaction are aliphatic and alicyclic as well as aromatic isocyanates.     

New radiolabelling chemistry: synthesis of phosphorus–[18F]fluorine compounds

The feasibility of synthesizing compounds containing the P–¹⁸F bond has been demonstrated by labelling the pesticide, cholinesterase inhibitor Dimefox (N,N,N′N′‐tetramethylphosphorodiamidic fluoride) with F‐18. Radiolabelling was achieved in high radiochemical yield (96%) by nucleophilic substitution of the chloro group attached to phosphorus, in the oxidation state P(V), by ¹⁸F^? (activated with tetrabutylammonium carbonate in acetonitrile). Given the large number of important biological molecules possessing phosphorus such as oligonucleotides, phospholipids as well as phosphorylated proteins, sugars and steroids, this new labelling chemistry may provide an additional route to radiolabelling these biologically important compounds for use in PET. Copyright © 2005 John Wiley & Sons, Ltd.     

Photo- und strahlenchemische Studien, 46. Mitt. Zur Photochemie des Isopropylaminophenazons im kristallinen Zustand und in wäßriger Lösung

Photochemical Studies, XLVI: Photochemistry of Isopropylaminophenazone in the Solid State and in Aqueous Solution Photolysis of 4-(isopropylamino)-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (isopropylaminophenazone) ( 1 ) in the solid state (A) or in aqueous solution (B) leads to: (A) N-isopropyl-N′-phenyloxamide, N′-acetyl-N′-methyl-N-(isopropylaminooxalyl)phenylhydrazine ( 2 ) and 2-(isopropylimino)-3-(methylimino)butyric acid anilide ( 3 ); (B) methyltartronic acid anilide isopropylamide ( 4 ), methyltartronic acid anilide methylamide ( 5 ), N-phenyl-N-(2-methylaminopropionyl)carbamic acid ( 6 ) and isopropylamine. The rearrangement of 1 to 3 is the first example of a solid state photoisomerisation in a 3-pyrazolin-5-one derivative.     

Synthese und komplexierende Eigenschaften symmetrischer N,N′-Tetra-(8-hydroxychinolyl-5-methyl)-α,ω-diaminoalkane

Synthesis and Complexing Properties of N,N,N′,N′-Tetrakis-(8-hydroxy-5-quinolylmethyl)-α,ω-diaminoalkanes A simple synthesis of N,N,N′,N′-tetrakis-(8-hydroxy-5-quinolylmethyl)-α,ω-diaminoalkanes, starting from 5-chloromethyl-8-hydroxyquinoline (basic material), and the complexing properties of these compounds are described.     

Nucleophile Addition von N,N′-Dimethylbenzamidin an aktivierte Doppelbindungen

Nucleophilic Addition of N,N′-Dimethylbenzanmidine to Activated Double Bonds Reaction of (ethoxymethylene)malodinitrile ( 1 ) with N,N′-dimethylbenzamidine ( 4 ) leads primarily to the formation of the zwitterionic 2 : 1 adduct 5 , which rearranges in boiling ethanol to yield the uncharged structural isomer 6 . In boiling methanol compound 7 is formed. The structures of 5,6 and 7 were determined by ¹H-NMR and ¹³C-NMR spectroscopy. N,N′-dimethylbenzamidine ( 4 ) reacts with ethyl propiolate ( 13 ) to yield the Michael adduct 14 .     

p,p′‐Dichlorodiphenyltrichloroethane promotes aerobic glycolysis via reactive oxygen species–mediated extracellular signal‐regulated kinase/M2 isoform of pyruvate kinase (PKM2) signaling in colorectal cancer cells

Aerobic glycolysis is crucial to tumor cells to acquire energy for proliferation and metastasis. Dichlorodiphenyltrichloroethane (DDT), which is a persistent organic pollutant, has been associated with colorectal cancer (CRC) progressions, but the influence of p,p′‐DDT on CRC cell metabolism remains unclear. This study showed that exposure to low concentrations of p,p′‐DDT from 10^?11 to 10^?7M for 48 hours significantly increased glucose uptake and lactate production in colorectal adenocarcinoma cells, which were accompanied by the upregulation of proteins associated with aerobic glycolysis including glucose transporter1, lactate dehydrogenase A, and PDH kinase. We found p,p′‐DDT elevated the expression and nucleus translocation of M2 isoform of pyruvate kinase (PKM2), which was responsible for p,p′‐DDT–induced enhancement of aerobic glycolysis. Moreover, extracellular signal‐regulated kinase (ERK1/2) activation by p,p′‐DDT modulated the impacts of p,p′‐DDT on PKM2 and aerobic glycolysis. Treatment of p,p′‐DDT increased intracellular reactive oxygen species (ROS). N‐acetyl‐L ‐cysteine, an ROS inhibitor, prevented p,p′‐DDT–induced promotion of aerobic glycolysis, ERK1/2 activation, upregulation, and nucleus translocation of PKM2. Taken together, these results demonstrated that p,p′‐DDT promotes aerobic glycolysis via ROS‐mediated ERK/PKM2 signaling.     

Elektrophile α-Amidoalkylierungen mit Enamiden nach einem neuen Aktivierungsverfahren mit O,O′-Dimethyldithiophosphorsäure

Electrophilic α-Amidoalkylation with Enamides According to a New Activation Procedure Using O,O′-Dimethyldithiophosphoric Acid The allylic amides 3a - d are rearranged to give enamides 4a - d using Pd-C as a catalyst. 4a - d and 10 are employed in an electrophilic α-amidoalkylation reaction with silyl enol ether 6 yielding the amido ketones 8a - d and 12 . The enamides are activated for this reaction by treatment with O,O′-dimethyldithiophosphoric acid ( 5 ) and SnCl₄.     

Zur Rotationshinderung N,N,N′-trisubstituierter Amidine

Hindered Rotation in N,N,N′-Trisubstituted Amidines Alkylation of N,N′-dimethylbenzamidine ( 4 ) with chloromethyl methyl ether and allyl iodide leads to the formation of the N-trisubstituted amidines 5a and 5d ; the lithium salt of 4 yields 5b and 5c with chloromethyl methyl sulfide and (chloromethyl)diethylamin, respectively. At temperatures up to 175°C no [1,3]sigmatropic rearrangement can be detected by ¹H-NMR spectroscopy; below room temperature a hindered rotation around the C-N single bond is observed.     

Relationship between intracellular Ca2+ and ROS during fluoride‐induced injury in SH‐SY5Y cells

The mechanisms underlying the neurotoxicology of endemic fluorosis still remain obscure. To explore lactate dehydrogenase (LDH) leakage, intracellular Ca²⁺ concentration ([Ca²⁺]_i) and reactive oxygen species (ROS) production induced by fluoride, human neuroblastoma (SH‐SY5Y) cells were incubated with sodium fluoride (NaF, 20, 40, 80 mg/L) for 24 h, with 40 mg/L NaF for 3, 6, 12, 18, 24 h, and N‐acetyl‐L ‐cysteine (NAC), ethyleneglycol‐bis‐(β‐aminoethyl ether)‐N,N,N′,N′‐tetraacetic acid (EGTA), 1,2‐bis(O‐aminophenoxy)ethane‐N,N,N′,N′‐tetraacetic acid tetra(acetoxymethyl) ester (BAPTA‐AM) alone or combined with fluoride (40 mg/L) respectively for 12 h in vitro. The results showed that the LDH levels in the 40 and 80 mg/L fluoride‐treated groups were significantly higher than that of the control group (in the test level of 0.05, the difference were statistical significance). [Ca²⁺]_i and ROS reached a peak at 3 h and 12 h respectively after exposure to 40 mg/L fluoride. Fluoride coincubated with NAC (antioxidant) dramatically decreased ROS and LDH levels compared with the fluoride only group (in the test level of 0.05, the difference were statistical significance). However, fluoride‐induced increase in [Ca²⁺]_i was not affected by NAC. BAPTA‐AM (intracellular calcium chelator) markedly lowered fluoride‐induced increase of [Ca²⁺]_i, ROS and LDH levels while EGTA (extracellular calcium chelator) have no effects on them. These results indicate that fluoride‐related Ca²⁺ release from the site of intracellular calcium storage causes the elevation of ROS contributing to the cytotoxicity in SH‐SY5Y cells. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.     

Reaktion von Cyansäureestern mit N- und N′-substituierten Carbonsäurehydraziden

Reaction of Cyanates with N- and N′-Substituted Carboxylic Hydrazides N-Substituted carboxylic hydrazides react with aryl cyanate, 2,2,2-trichloroethyl cyanate and 2,2,2-trifluoroethyl cyanate 2 to form the 1-acylisosemicarbazides 7 . On treatment of the N′-substituted (aralkyl, alkyl) carboxylic hydrazides 8 with the cyanates listed, the 2-imino-1,3,4-oxa-diazolines 10 are obtained by elimination of phenol or 2,2,2-trihalogenoethanol. Reaction between 8 and cyanogen bromide and alkylation of the 2-amino-1,3,4-oxadiazoles 5 also yield 10 . Two derivatives of 10 yielded the dimers 17 .     

Synthesis of Some N,N′‐Diacylhydrazine Derivatives with Radical‐Scavenging and Antifungal Activity

A series of N,N′‐diacylhydrazines were prepared and their structures were confirmed by ¹H NMR, MS and FTICR‐MS. They were tested radical‐scavenging activity in vitro. The preliminary bioassays of title compounds showed that two compounds had excellent radical‐scavenging activity comparable with vitamin C, while the activity is highly relative to the substituents. Surprisingly, several compounds also exhibit favorable fungicidal activities. To further explore the comprehensive structure–activity relationships about the fungicidal activity, a three‐dimensional quantitative structure–activity relationship analysis using the method of comparative molecular field analysis was performed.     

Delayed Treatment with YM90K,an AMPA Receptor Antagonist,Protects against Ischaemic Damage after Middle Cerebral Artery Occlusion in Rats

The neuroprotective effect of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride] has been examined in a rat middle cerebral artery occlusion model. Intravenous infusion of YM90K (2·5–20mgkg^?1h^?1 for 4 h) starting immediately after occlusion of the middle cerebral artery significantly reduced the cortical infarct volume 24 h after occlusion compared with the control group. The protection at the highest dose was 39% (P<0·05). Similar protective effects were observed when YM90K (20mgkg^?1h^?1 for 4 h) was delayed up to 2 h after middle cerebral artery occlusion (45% reduction, P<0·05). CNS1102 [N-(1-naphthyl)-N′-(3-ethylphenyl)-N′-methylguanidine hydrochloride], a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also reduced the cortical infarct volume when 1·3mgkg^?1 was administered by intravenous bolus injection immediately after middle cerebral artery occlusion, followed by intravenous infusion at 0·785 mgkg^?1h^?1 for 4 h (35% reduction, P<0·05). This neuroprotective effect was not observed when administration was delayed 1 h after middle cerebral artery occlusion. These results suggest that AMPA receptors might play a more important role than NMDA receptors in the late development of neuronal cell damage after focal cerebral ischaemia and that AMPA receptor blockade would be one beneficial strategy in treating acute stroke.     

Über die Reaktion von Quadratsäure mit Carbodiimiden

Reactions of Squaric Acid with Carbodiimides Reactions of squaric acid ( 5 ) with carbodiimides 2 yield N-(2-hydroxy-3,4-dioxo-1-cyclobutenyl)-N,N'-dialkylureas 6 , or N,N'-diarylsquaric acid diamides 8. Depending on the conditions, squaric acid reacts with N-isopropyl-N'-phenylcarbodiimide ( 2f ) to yield N-(2-hydroxy-3,4-dioxo-1-cyclobutenyl)-N'-isopropyl-N-phenylurea ( 17 ) or 3,4-bis-(3-isopropyl-1-phenylureido)-3-cyclobutene-1,2-dione ( 19 ).     

Thion- und Dithioester, 52. Mitt.: Zur Reaktion von Dithionmalonestern mit N,N-Dimethylformamidacetalen

Thiono and Dithio Esters, LII¹⁾: Reaction of Dithiono Malonates with N,N-Dimethylformamide Acetals The reaction of the dithiono malonates 1 with the formamide acetals 2 leads to the 2-dialkylaminomethylene dithionomalonates 4 and the thiono acrylates 6 . The condensation of 4 with hydrazines gives rise to the pyrazoles 7 and 8 , with hydroxylamine sulfonic acid to the isothiazoles 10 , and with amidines to the pyrimidines 11 - 13 .     

Antimykotische Wirkstoffe, 7. Mitt. Kernsubstituierte N-(1-Adamantyl)-N′-phenylthioharnstoffe

Antimycotic Agents, VII: N-(1-Adamantyl)-N′-phenylthiourea Derivatives with Substituents on the Aromatic Nucleus N-(1-Adamantyl)-N′-phenylthiourea derivatives 3 carrying methylthio groups, fluorine atoms or a trifluoromethyl substituent on the aromatic nucleus may be obtained by nucleophilic addition of an appropriately substituted aniline derivative 2 to (1-adamantyl) isothiocyanate ( 1 ).