Practical synthesis of a functionalized 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The synthesis of a functionalized 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid has been performed in 10 steps from the readily available dimedone. Only three purifications by flash chromatography are required through the whole sequence. The key step is the reaction between a dimedone derivative and a chlorotetrolic ester, that gives a tetrasubstituted benzene ring (through a Diels-Alder/retro- Diels-Alder process) bearing the substituents in the suitable positions for further functionalization. (C) 2012 Elsevier Ltd. All rights reserved.

Toll-like receptors 2, 3 and 4 and thymic stromal lymphopoietin expression in fatal asthma

Background Airway inflammation in asthma involves innate immune responses. Toll-like receptors (TLRs) and thymic stromal lymphopoietin (TSLP) are thought to be involved in airway inflammation, but their expression in asthmatics both large and small airways has not been investigated. Objective To analyse the expression of TLR2, TLR3, TLR4 and TSLP in large and small airways of asthmatics and compare their expression in smoking and non-smoking asthmatics; to investigate whether TLR expression is associated with eosinophilic or neutrophilic airway inflammation and with Mycoplasma pneumoniae and Chlamydophila pneumoniae infection. Methods Using immunohistochemistry and image analysis, we investigated TLR2, TLR3, TLR4 and TSLP expression in large and small airways of 24 victims of fatal asthma, FA, (13 non-smokers, 11 smokers) and nine deceased control subjects (DCtrl). TLRs were also measured in 18 mild asthmatics (MA) and 12 healthy controls (HCtrl). M. pneumoniae and C. pneumoniae in autopsy lung tissue were analysed using real-time polymerase chain reaction. Airway eosinophils and neutrophils were measured in all subjects. Results Fatal asthma patients had higher TLR2 in the epithelial and outer layers of large and small airways compared with DCtrls. Smoking asthmatics had lower TLR2 levels in the inner and outer layers of the small airways than non-smoking asthmatics. TSLP was increased in the epithelial and outer layers of the large airways of FA. FA patients had greater TLR3 expression in the outer layer of large airways and greater TLR4 expression in the outer layer of small airways. Eosinophilic airway inflammation was associated with TLR expression in the epithelium of FA. No bacterial DNA was detected in FA or DCtrls. MA and HCtrls had only a small difference in TLR3 expression. Conclusions and Clinical Relevance Increased expression of TLR 2, 3 and 4 and TSLP in fatal asthma may contribute to the acute inflammation surrounding asthma deaths.

Formation of thin luminescent Eu3+-LB films by in situ coordination with 2,3,5,6-tetra(2 '-pyridyl)pyrazine and 1-octadecanol in pure and mixed Langmuir monolayers

The in situ complexation between 2,3,5,6-tetra(2-pyridyl)pyrazine (tppz) molecules and europium ions at the air-liquid interface by means of mixed 1-octadecanol Langmuir films is reported. These films were transferred to solid supports by means of the Langmuir-Blodgett (LB) technique. The EDS maps attested the homogeneity of the LB films as well as the presence of the europium ions. The mixed alcohol/tppz LB film contained a larger amount of europium ions as compared to the pure octadecanol LB film. This work reports the production of a thin luminescent Eu3+ film containing europium ions using only alcohol molecules as ligands an unexpected result, since it is well known that there is an occurrence of non-radiative deactivation of excited europium by hydroxyl groups. Europium ion multiple binding sites were detected from lifetime decay measurements of these films in the presence of tppz molecules. (C) 2012 Elsevier B.V. All rights reserved.

Synthese, n.c.a. 18F-Markierung und Evaluierung von Antagonisten der Strychnin-unempfindlichen-Glycinbindungsstelle auf Basis der 4-Amino-5,7-Dichlor-1,2,3,4-Tetrahydro-Chinolin-2-Carbonsäure

ZUSAMMENFASSUNGDer glutamaterge N-Methyl-D-aspartat-Rezeptor (NMDA) ist ein wichtiger ionotroper Rezeptor, der die exzitatorische synaptische Transmission im zentralen Nervensystem von Säugetieren vermittelt. Der NMDA-Rezeptor nimmt unter den Glutamatrezeptoren dabei eine Sonderstellung ein, da er mit einer Reihe von neurodegenerativen Erkrankungen wie dem Morbus Parkinson, dem Morbus Huntington, dem Morbus Alzheimer, der Schizophrenie und der Epilepsie in Zusammenhang gebracht wird. Daher besteht ein großes Interesse an der Entwicklung geeigneter 18F-markierter NMDA-Rezeptorliganden zur nicht-invasiven Visualisierung des NMDA-Rezeptorkomplexes mittels der Positronenemissionstomographie.Die 19F-Analoga ADTC1, tADTC1 und tADTC3 - 5 und das nicht-fluorierte 12C-Analogon tADTC2 wurden synthetisiert und ihre in-vitro Affinität und Lipophilie bestimmt. Mit Ausnahme von ADTC1 und tADTC5 die mikromolare Affinitäten besitzen, haben die Liganden in [H-3]MDL-105,519 Rezeptorbindungsassays niedrige nanomolare Affinitäten für die Glycinbindungsstelle. Die Lipophilie der Verbindungen wurde mit drei verschiedenen Verfahren untersucht und ergab logD7,4-Werte von ungefähr 1 für cADTC1 und tADTC1 – 4, während tADTC5 mit einem logD7,4 von –1,15 eine sehr niedrige Lipophilie aufwies. Die Radiosynthesen der 18F-Liganden wurden hinsichtlich der Umsetzung der Markierungsvorläufer mit 2-[F-18]Fluorethyltosylat oder [F-18]Fluorid untersucht und optimiert. Die höchsten radiochemischen Ausbeuten von ungefähr 90% wurden, unter Verwendung von NaOH als Hilfsbase, bei der 18F-Fluorethylierung von t[F-18]ADTC4 und t[F-18]ADTC5 mit 2-[F-18]Fluorethyltosylat erzielt.

L'espressione dell'enzima Indoleamina 2,3-Diossigenasi come meccanismo immunoregolatore in cellule dentritiche normali e leucemiche

L’enzima indoleamina 2,3-diossigenasi (IDO) catalizza la conversione dell’aminoacido essenziale triptofano in chinurenine. Questa proprietà conferisce a IDO la capacità di inibire la risposta immunitaria sia causando la deplezione dal microambiente di triptofano, che è necessario ai linfociti T per proliferare ed espandersi, sia producendo metaboliti che possono causare l’apoptosi dei linfociti T. Nel presente studio è stata indagata la funzione di IDO in cellule dendritiche normali e leucemiche. Lo studio dell’espressione di IDO in cellule dendritiche normali ha permesso di osservare che, quando immature, IDO è poco espresso, mentre durante la maturazione IDO viene up-regolato. In particolare, l’incremento nell’espressione di IDO non è strettamente legato al livello di maturazione, ma alla qualità dello stimolo maturativo. Infatti uno stimolo endogeno come il ligando di CD40 ha una scarsa efficacia nell’up-regolazione di IDO, uno stimolo batterico come l’LPS ha un’efficacia intermedia, mentre uno stimolo rappresentato da citochine pro-infiammatorie ha un’efficacia massima. L’espressione di IDO risulta direttamente propozionale alla produzione di chinurenine, all’inibizione della proliferazione dei linfociti T e all’induzione di una popolazione di linfociti T regolatori. Lo studio dell’espressione di IDO in cellule dendritiche leucemiche ha permesso di osservare che IDO è espresso a un livello intermedio nelle cellule dendritiche leucemiche immature e viene up-regolato durante la maturazione. La conseguenza principale dell’espressione di IDO in cellule dendritiche leucemiche è l’induzione di una popolazione di linfociti T regolatori fortemente in grado di limitare sia la risposta CD4+ che la risposta CD8+ anti-leucemica e capaci di inibire la maturazione di altre cellule dendritiche. Nel complesso, i dati emersi da questo studio hanno permesso di concludere che, in cellule dendritiche normali, IDO rappresenta un meccanismo tollerogenico la cui intensità di espressione è correlata all’intensità dello stimolo attivatorio da controbilanciare, a cui è sottoposta la cellula dendritica. Nelle cellule dendritiche leucemiche IDO rappresenta un meccanismo di tumor-escape in grado di inibire l’attivazione di cellule dendritiche, linfociti CD4+ e linfociti CD8+.

2,3-Divinyl- und 2-Aryl-3-vinylindole als Bausteine zu Carbazolen und Versuche zur photochemischen und Ultraschall-induzierten 1,6-Elektrocyclisierung

Es wurden neue funktionalisierte Carbazole und anellierte Benzo[a]carbazole als potentielle pharmakologische Therapeutika durch 1,6-pi-Elektrocyclisierung auf photo-chemischem, thermischem und sonochemischem Weg synthetisiert und die Synthesemethoden der 1,6-pi-Elektrocyclisierung sowie der 2,3-Divinylindole und der 2-Aryl-3-vinylindole als entsprechende Ausgangsprodukte validiert und evaluiert. Es gelang weder das nach den Woodward-Hoffmann-Regeln erwartete primäre Cyclisierungsprodukt mit Indolochinodimethanstruktur noch die Existenz des in einer photochemischen Abfangreaktion daraus resultierenden Cycloprodukts NMR-spektroskopisch nachzuweisen, um den stereochemischen Verlauf der Cyclisierung vorherzusagen. Ergebnisse der quantenchemischen Berechnungen der Eduktmoleküle (AO-Koeffizienten der MO's, HOMO/LUMO-Energien) sowie der Übergangszustandsgeometrien der Cyclisierungen decken sich mit den experimentellen Daten. Divinyl- und 2-Aryl-3-vinylindole sind als Systeme mit Hexatriensymmetrie aufzufassen, deren Cyclisierungsverhalten sich mit den Woodward-Hoffmann-Regeln beschreiben läßt. Im Vergleich der verschiedenen 1,6-pi-Elektrocyclisierungsmethoden zeigte sich, daß die photochemische Variante eine elegante Synthesemethode darstellt, um funktionalisierte Carbazole und Benzo[a]carbazole mit unterschiedlichen pharmakologischen Aktivitäten unter schonenden Reaktionsbedingungen mit den vergleichbar höchsten Ausbeuten zu erhalten. Demgegenüber lieferten die Ultraschallreaktionen keine nachweisbaren Cyclisierungsprodukte. Die thermische Cyclisierung führte zur Gruppe der 1,2-Dihydrocarbazole. Sie bildeten sich in einer Folgereaktion durch [1,5s]-H-Verschiebung aus dem primär entstandenen Woodward-Hoffmann-Cyclisierungsprodukt. In abschließenden DNA-Bindestudien mit verschiedenen Testsystemen zeigte keine der synthetisierten Testsubstanzen DNA-Bindungsaktivität.

Espressione dell'Enzima ad Azione Immunoregolatoria Indoleamina 2,3-Diossigenasi nella Leucemia Mieloide Acuta dell'Adulto: correlazioni Clinico-Biologiche

L’enzima IDO interviene nella via di degradazione del triptofano, essenziale per la vita cellulare; l’iperespressione di IDO favorisce la creazione di un microambiente immunotollerante. Nelle LAM IDO è funzionalmente attivo nelle cellule blastiche e determina l’acquisizione di un fenotipo regolatorio da parte delle cellule T alloreattive; l’espressione della proteina aumenta in modo consensuale con l’evoluzione clinica della patologia. Scopo della Tesi è indagare l’esistenza di una correlazione tra l’iperespressione di IDO da parte delle cellule leucemiche, le caratteristiche di rischio alla diagnosi e l’outcome dei pazienti. Sono stati esaminati 45 pazienti adulti affetti da LAM afferiti all’Istituto di Ematologia di Bologna. I pazienti sono stati stratificati a seconda di: età di insorgenza della leucemia, secondarietà a Mielodisplasia o radio chemioterapia, iperleucocitosi, citogenetica, biologia molecolare (sono state valutate le alterazioni a carico dei geni FLT3 ed NPM). I pazienti sono stati analizzati per l’espressione del gene IDO mediante RT-PCR, seguita da Western Blot, allo scopo di stabilire la presenza di una proteina attiva; successivamente si è proceduto a verificare l’esistenza di una correlazione tra l’espressione di IDO e le caratteristiche di rischio alla diagnosi per identificare una relazione tra l’espressione del gene ed un subset di pazienti a prognosi favorevole o sfavorevole. Dei 45 pazienti adulti affetti da LAM il 28,9% è risultato negativo per l’espressione di IDO, mentre il rimanente 71,1% è risultato positivo ed è stato suddiviso in tre ulteriori categorie, in base ai livelli di espressione. I dati non sembrano al momento suggerire l’esistenza di una correlazione tra l’espressione di IDO e le caratteristiche di rischio alla diagnosi. Nel gruppo di pazienti ad elevata espressione di IDO si riscontra un rate di resistenza alla chemioterapia di induzione più elevato, con una quota di pazienti resistenti pari al 71,4%, contro il 23,1% nel gruppo di pazienti IDO-negativi.

Tailoring, synthesis and structure-property relationships of 2,3-thienoimide based molecular materials

Organic molecular semiconductors are subject of intense research for their crucial role as key components of new generation low cost, flexible, and large area electronic devices such as displays, thin-film transistors, solar cells, sensors and logic circuits. In particular, small molecular thienoimide (TI) based materials are emerging as novel multifunctional materials combining a good processability together to ambipolar or n-type charge transport and electroluminescence at the solid state, thus enabling the fabrication of integrated devices like organic field effect transistors (OFETs) and light emitting transistor (OLETs). Given this peculiar combination of characteristics, they also constitute the ideal substrates for fundamental studies on the structure-property relationships in multifunctional molecular systems. In this scenario, this thesis work is focused on the synthesis of new thienoimide based materials with tunable optical, packing, morphology, charge transport and electroluminescence properties by following a fine molecular tailoring, thus optimizing their performances in device as well as investigating and enabling new applications. Investigation on their structure-property relationships has been carried out and in particular, the effect of different π-conjugated cores (heterocycles, length) and alkyl end chain (shape, length) changes have been studied, obtaining materials with enhanced electron transport capability end electroluminescence suitable for the realization of OFETs and single layer OLETs. Moreover, control on the polymorphic behaviour characterizing thienoimide materials has been reached by synthetic and post-synthetic methodologies, developing multifunctional materials from a single polymorphic compound. Finally, with the aim of synthesizing highly pure materials, simplifying the purification steps and avoiding organometallic residues, procedures based on direct arylation reactions replacing conventional cross-couplings have been investigated and applied to different classes of molecules, bearing thienoimidic core or ends, as well as thiophene and anthracene derivatives, validating this approach as a clean alternative for the synthesis of several molecular materials.

Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

2,3-Dichloro-1,4-hydroquinone 2,3-dichloro-1,4-benzoquinone monohydrate: a quinhydrone-type 1:1 donor-acceptor [D-A] charge-transfer complex

In the crystal structure of the title compound (systematic name: 2,3-dichlorobenzene-1,4-diol 2,3-dichlorocyclohexa-2,5-diene-1,4-dione monohydrate), C(6)H(4)Cl(2)O(2)center dot C(6)H(2)Cl(2)O(2)center dot H(2)O, the 2,3-dichloro-1,4-hydroquinone donor (D) and the 2,3-dichloro-1,4-benzoquinone acceptor (A) molecules form alternating stacks along [100]. Their molecular planes [maximum deviations for non-H atoms: 0.0133 (14) (D) and 0.0763 (14) angstrom (A)] are inclined to one another by 1.45 (3)degrees and are thus almost parallel. There are pi-pi interactions involving the D and A molecules, with centroid-centroid distances of 3.5043 (9) and 3.9548 (9) angstrom. Intermolecular O-H center dot center dot center dot O hydrogen bonds involving the water molecule and the hydroxy and ketone groups lead to the formation of two-dimensional networks lying parallel to (001). These networks are linked by C-H center dot center dot center dot O interactions, forming a three-dimensional structure.

The MSSM with a softly broken U(2)^3 flavor symmetry

In this article we review the phenomenological consequences of radiative flavor-violation (RFV) in the MSSM. In the model under consideration the U(3)^3 flavor symmetry of the gauge sector is broken in a first step to U(2)^3 by the top and bottom Yukawa couplings of the superpotential (and possibly also by the bilinear SUSY-breaking terms). In a second step the remaining U(2)^3 flavor symmetry is softly broken by the trilinear A-terms in order to obtain the measured quark masses and the CKM matrix of the Standard Model (SM) at low energies. The phenomenological implications of this model depend on the actual choice of the SUSY breaking A-terms. If the CKM matrix is generated in the down sector (by A^d), Bs->mu^+mu^- receives non-decoupling contributions from Higgs penguins which become important already for moderate values of tan(beta). Also the Bs mixing amplitude can be significantly modified compared to the SM prediction including a potential induction of a new CP-violating phase (which is not possible in the MSSM with MFV).