Probing acid-amide intermolecular hydrogen bonding by NMR spectroscopy and DFT calculations

Benzene carboxylic acids and Benzamide act as their self-complement in molecular recognition to form inter-molecular hydrogen bonded dimers between amide and carboxylic acid groups, which have been investigated by H-1, C-13 and N-15 NMR spectroscopy. Extensive NMR studies using diffusion ordered spectroscopy (DOSY), variable temperature 1D, 2D NMR, established the formation of heterodimers of benzamide with benzoic acid, salicylic acid and phenyl acetic acid in deuterated chloroform solution. Association constants for the complex formation in the solution state have been determined. The results are ascertained by X-ray diffraction in the solid state. Intermolecular interactions in solution and in solid state were found to be similar. The structural parameters obtained by X-ray diffraction studies are compared with those obtained by DFT calculations. (C) 2012 Elsevier B.V. All rights reserved.

Solvent extraction of americium and europium ions by amide-derivatized polyethers from picric acid aqueous solution

The extraction of Am3+ and Eu3+ from picric acid aqueous solution by N,N-1,2-ethanediyl-bis[2-(N,N-diphenyl-carbamoyl-methoxy)-benzamide] was investigated by a radioactive tracer technique. The composition of the extracted species has been determined as ML(Pic)(3) (M = Eu, Am). The effect of various parameters such as pH, organic diluents, different extractants, picric acid concentration and extractants concentration on the extraction of Am3+ and Eu3+ has been studied. The extraction equilibrium mechanism has been also evaluated and discussed.

Effect of main-chain rigidity on the phase transitional behavior of comblike polymers

The influence of the rigidity of polymer backbones on the side-chain crystallization and phase transition behavior was systematically investigated by a combination of differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), Fourier transform infrared spectroscopy (FTIR), and high-resolution solid-state nuclear magnetic resonance spectroscopy (NMR). DSC investigation indicated that the crystallization number of alkyl carbon atoms of the side chains grafted onto the rigid polymer backbone, poly(p-benzamide) (PBA), is much lower than that of the alkyl carbon atoms of the side chains grafted onto the flexible polymer backbone, poly(ethyleneimine) (PEI), implying that the conformational state of the polymer backbones has a strong effect on the side-chain crystallization behavior in comblike polymers. WAXD and FTIR results proved that these two comblike polymers pack into hexagonal (PBA18C) and orthorhombic (PEI18C) crystals, respectively, depending on the adjusting ability of the polymer backbones for particular conformational states. It was also found that the presence of the crystalline-amorphous interphase (delta = 31.6 ppm) in PBA18C detected by solid-state C-13 NMR spectroscopy can be attributed to the rigid PBA backbone, which restricts the mobility of the alkyl side chains.

Some aspects of the chemistry of Reissert compounds / |nDurga Prasad Aysola. -- 260 St. Catharines [Ont. : s. n.],

1-(0- and m-Ohlorobenzoyl)isoquinolines have been synthesized by two routes involving Reissert compounds. One route involves condensation of 2-benzoyl-l,2-dihydroisoquinaldonitrile with the appropriate chlorobenzaldehyde and the second involves rearrangement of the appropriate Z-(chlorobenzoyl)-l,Z-dihydroisoquinaldonitrile under basic conditions. The action of potassamide in anhydrous liquid ammonia on both ketones gave unexpectedly N-(l-isoquinolyl)benzamide (67) as the major product and the use of dibenzo-18-crown-6-ether 98% substantially improved the yd..e.ld in the case of l-chloroketone. This amide (67) exhibits unusual hydrogen bonding. 1-(o-chlorobenzoyl)-6,7-dimethoxyisoquinoline (79) was prepared in very s,amll quantities by the route involving condensation of 2-benzoyll, Z-dihydro-6,7-dimethoxyisoquinaldonitrile with o-chlorobenzaldehyde. The poor yields are due to the instability of the anion of 2-benzoyl1, Z-dihydro-6,7-dimethoxyisoquinaldonitrile. Attempted preparation of the ketone (79) by rearrangement of 2-(o-chlorobenzoyl)-l,2-dihydro6,7- dimethoxyisoquinaldonitrile under basic conditions yielded the start~ng material (Reissert compound) and 6,7-dimethoxyisoquinoline. The action of potassamide in anhydrous liquid ammonia on l-(o-bromo-4,5-dimethoxybenzoyl)isoquinoline (85), which was prepared by the route involving the condensation of 2-benzoyl-l,4-dihydroisoquinaldonitrile with o-bromo-4,5-dimethoxybenzaldehyde, gave two products, which have not yet been identified. The ketone (85) and its precursors are interest~ng in that their 20 eV and 70 eV mass spectra do not show molecular ions.

Studies toward the total synthesis of natural and unnatural aeruginosins

Nous avons démontré l’utilité du groupement protecteur tert-butylsulfonyle (N-Bus) pour la chimie des acides aminés et des peptides. Celui-ci est préparé en deux étapes, impliquant la réaction d’une amine avec le chlorure de tert-butylsulfinyle, suivie par l’oxydation par du m-CPBA, pour obtenir les tert-butylsulfonamides correspondants avec d’excellents rendements. Le groupement N-Bus peut être clivé par traitement avec 0.1 N TfOH/DCM/anisole à 0oC en 10h pour régénérer le sel d’ammonium. Une variété d’acides aminés N-Bus protégés ainsi que d’autres aminoacides peuvent alors être utilisés pour préparer divers dipeptides et tripeptides. A l’exception du groupe N-Fmoc, les conditions de déprotection du groupe N-Bus clivent également les groupements N-Boc, N-Cbz et O-Bn. Une déprotection sélective et orthogonale des groupes N-Boc, N-Cbz, N-Fmoc et O-Bn est également possible en présence du groupe protecteur N-Bus. Le nouvel acide aminé non-naturel (3R, 2R) 3–méthyl-D-leucine (β-Me-Leu) et son régioisomère 2-méthyle ont été synthétisés par ouverture d’une N-Ts aziridine en présence d’un excès de LiMe2Cu. Chacun des régioisomères du mélange (1:1,2) a été converti en la méthylleucine correspondante, puis couplé à l’acide D-phényllactique puis au motif 2-carboxyperhydroindole 4-amidinobenzamide en présence de DEPBT. Des élaborations ultérieures ont conduit à des analogues peptidiques non-naturels d’aeruginosines telles que la chlorodysinosine A. Les deux analogues ont ensuite été évalués pour leur activité inhibitrice de la thrombine et la trypsine. La présumée aeruginosine 3-sulfate 205B et son anomère β ont été synthétisés avec succès à partir de 5 sous-unités : la 3-chloroleucine, l’acide D-phényllactique, le D-xylose, le 2-carboxy-6-hydroxyoctahydroindole et l’agmatine. La comparaison des données RMN 1H et 13C reportées avec celles obtenues avec l’aeruginosine synthétique 205B révèle une différence majeure pour la position du groupe présumé 3'-sulfate sur l’unité D-xylopyranosyle. Nous avons alors synthétisés les dérivés méthyl-α-D-xylopyranosides avec un groupement sulfate à chacune des positions hydroxyles, afin de démontrer sans ambiguïté la présence du sulfate en position C-4' par comparaison des données spectroscopiques RMN 1H et 13C. La structure de l’aeruginosine 205B a alors été révisée. Une des étapes-clés de cette synthèse consiste en la formation du glycoside avec le groupe hydroxyle en C-6 orienté en axial sur la sous-unité Choi. Le 2-thiopyridylcarbonate s’est avéré une méthode efficace pour l’activation anomérique. Le traitement par AgOTf et la tétraméthylurée en solution dans un mélange éther-DCM permet d’obtenir l’anomère α désiré, qui peut alors être aisément séparé de l’anomère β par chromatographie

A micelle nucleation model for the interaction of dodecyl sulphate with Lys49-phospholipases A(2)

Bothropstoxin-I (BthTx-I) is a Lys49-PLA(2) from the venom of Bothrops jararacussu that lacks detectable catalytic activity, yet causes rapid Ca2+-independent membrane damage. With the aim of understanding the interaction between BthTx-I and amphiphilic molecules, we have studied the interaction of sodium dodecyl sulphate (SDS) with the protein. Circular dichroism and attenuated total reflection Fourier-transform infrared spectra of BthTx-I reveal changes in the alpha-helical organization of the protein at an SDS/BthTx-I molar ratio of 20-25. At SDS/BthTx-I ratios of 40-45 the alpha-helices return to a native-like conformation, although fluorescence emission anisotropy measurements of 2-amino-N-hexadecyl-benzamide (AHBA) demonstrate that the total SDS is below the critical micelle concentration when this transition occurs. These results may be interpreted as the result of SDS accumulation by the BthTx-I homodimer and the formation of a pre-micelle SDS/BthTx-I complex, which may subsequently be released from the protein surface as a free micelle. Similar changes in the alpha-helical organization of BthTx-I were observed in the presence of dipalmitoylphosphatidylcholine liposomes, suggesting that protein structure transitions coupled to organization changes of bound amphiphiles may play a role in the Ca2+-independent membrane damage by Lys49-PLA(2)s. (c) 2006 Elsevier B.V. All rights reserved.

Acute toxicity and environmental risk of teflubenzuron to Daphnia magna, Poecilia reticulata and Lemna minor in the absence and presence of sediment

This study aimed to estimate the acute toxicity of teflubenzuron (1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea) (TFB) for Daphnia magna, Lemna minor and Poecilia reticulata, in the absence and presence of sediment; evaluate the effect of sediment on the TFB bioavailability; and to classify this insecticide according to its environmental poisoning risk for agricultural and aquaculture uses. The tests of TFB acute toxicity were conducted in static system in a completely randomized design with increasing TFB concentrations, and a control group. The TFB has been classified according to the estimated values of EC50 and LC50 by its acute toxicity and environmental risk. The sediment significantly reduced toxicity and bioavailability of TFB in water column. Therefore, the insecticide can be classified as being highly toxic to Daphnia magna, which means the agricultural and aquacultural uses of TFB pose a high risk of environmental toxicity to non-target organisms. However, it was practically non-toxic to L. minor and P. reticulata. © 2013 Copyright Taylor and Francis Group, LLC.

In vitro targeting of Polo-like kinase 1 in bladder carcinoma: Comparative effects of four potent inhibitors

Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and preclinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs. © 2013 Landes Bioscience.

Efeito da alizaprida intravenosa sobre o prurido provocado pela morfina administrada por via subaracnóidea

Pós-graduação em Anestesiologia - FMB

Antifungal Compounds Produced by Colletotrichum gloeosporioides, an Endophytic Fungus from Michelia champaca

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

CHEMICAL CONSTITUENTS FROM RED ALGAE Bostrychia radicans (Rhodomelaceae): NEW AMIDES AND PHENOLIC COMPOUNDS

This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N, 4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl)-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl)-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl)-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family.

Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae): new amides and phenolic compounds

This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N,4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl)-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl)-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl)-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family.

Synthese, Tritierung, 99m Tc-Markierung und Evaluierung von Benzamid-Derivaten zur Visualisierung der D 2, D 3-Rezeptoren

Die Diagnose und Therapie von neurodegenerativen Krankheiten, wie beispielsweise Morbus Parkinson besitzt in der heutigen Gesellschaft eine immer größere Bedeutung. Über moderne, bild¬gebende nuklear¬medizinische Verfahren wie SPECT und PET ist es mit geeigneten Radioliganden möglich, Morbus Parkinson vor dem Auftreten von Symptomen zu diagnostizieren. Ein wichtiger Ansatzpunkt zur Diagnose von Morbus Parkinson ist die Visualisierung der postsynaptischen Dopamin-Rezeptoren über radioaktiv (11C, 18F, 123I) markierte Benz¬amid-Derivate. Auf Grundlage der (S)-Pyrolidin-2,3-dimethoxy-Benzamid-Struktur des 18F-Liganden Fallypride wurden verschiedene 99mTc-markierte Benzamid-Derivate als potentielle Radio¬liganden zur Parkinson-Diagnostik entwickelt. Um das Potential von Metall-konjugierten Benzamiden abschätzen zu können, wurden zunächst einfache Vergleichssubstanzen entwickelt. Diese sollten die Einführung eines Chelators simulieren und wurden hierfür hinsichtlich ihrer in vitro-Bindungsaffinitäten zu den Dopamin-, Serotonin- und adrenergen Rezeptoren evaluiert. Die zunächst entwickelten Derivate mit unterschiedlichen Kettenlängen zur Kopplung des Chelators zeigten für die Propylkette Affinitäten im nanomolaren Bereich. Im Anschluss sollten basierend auf diesen Ergebnissen vier verschiedene Chelatoren (Carbony-Cyclopentadienyl, Amido-Cyclopentadienyl, 2-Pyridyl-Imin und N2S2) über eine Propylkette an die 5-Position der Benzamidgrundstruktur gekoppelt werden. Die geplante Synthese des Carbonyl-Cyclopentadienyl-Derivates gelang jedoch nicht. Für die weiteren Chelatoren (Amido-Cyclopentadieny, 2-Pyridyl-Imin und N2S2) konnten die jeweiligen Markierungs¬vorläufer und Rhenium-Komplexe dargestellt werden, die ebenfalls hinsichtlich ihrer Bindungs¬affinitäten evaluiert wurden. Die erzielten Affinitäten zeigten, dass eine Über¬tragung der Affinitäten der einfachen Vergleichssubstanzen auf die komplexeren Metall-Benzamide nicht möglich war. Insbesondere der N2S2-Rhenium-Komplex besitzt nur noch geringe Affinität (490 - 900 nM) zu den D2- und D3-Rezeptoren. Die mittel-affinen 2-Pyridyl-Imin- und Amdio¬cyclopentadien-Komplexe wurden mit 99mTc markiert und die Markierungsausbeute hinsichtlich Reaktionstemperatur, Markierungs-vorläuferkonzentration und Heizmethoden optimiert. Dabei konnte der Imin-Komplex quantitativ mittels fac-[99mTc(CO)3(H2O)3]+ in 30 Minuten bei 45°C markiert werden. Der Amido-Cyclopentadien-Komplex konnte über die Umsetzung des Ferrocen-Markierungsvorläufer mit Mn(CO)5Br und [99mTcO4]- in Ausbeuten von bis zu 60 % markiert werden. Im Anschluss an die Markierungen wurden die 99mTc-Komplexe über HPLC isoliert und in in vitro-Auto¬radiographien von Rattenhirnschnitten weiter evaluiert. Die erhaltenen Ergebnisse bestätigten die für die Rhenium-Komplexe erzielten Affinitäten und zeigten keine spezifische Anreicherung in bestimmten Hirnarealen. Aus diesen Ergebnissen kann ge¬schlossen werden, dass die dargestellten 99mTc-Benzamide aufgrund mangelnder Affinitäten und einer hohen unspezifischen Bindung keine geeigneten Liganden zur Darstellung der D2- und D3- Rezeptoren sind. Um die dargestellten 99mTc-Benzamide mit [18F]Fallypride vergleichen zu können, wurde zusätzlich [3H]Fallypride dargestellt. Hierfür wurde zunächst der Nor-Markierungsvor¬läufer synthetisiert und die Markierungsausbeute optimiert. Die finale Umsetzung mit [3H]Methylnosylat ergab nach HPLC-Aufreinigung 15 mCi [3H]Fallypride mit einer radio¬chemischen Reinheit von >99,5 %. Erste Autoradiographien zeigten eine hohe Anreicherung des Liganden im Striatum, verbunden mit einer sehr niedrigen unspezifischen Bindung.

Synthese und Untersuchung aromatischer Amide und aramidbasierter Blockcopolymere

Aromatische Amide mit p-Verknüpfung bilden die wohl steifste und härteste Klasse organischer Moleküle. Ihre Oligomere und Polymere sind Materialien mit extremer Stabilität und chemischer Robustheit. Die vorliegende Arbeit beschreibt die Synthese wohldefinierter Oligo-(p-benzamid)e (OPBA) bis zum Hepta-(p-benzamid), deren Kristallstruktur und thermisches Verhalten eingehend untersucht werden. Ihre besondere Steifigkeit wird im Folgenden genutzt, um Stab-Knäuel-Copolymere mit wohldefiniertem OPBA-Stab-Block herzustellen. Das Aggregationsverhalten dieser Copolymere wird näher beschrieben und die Aggregate mittels Rasterkraftmikroskopie (RKM) visualisiert und charakterisiert. Ein Schwerpunkt der durchgeführten Forschung befasst sich mit dem Einflu"s chemischer Variationen von Knäuel- und Stabblock auf die Aggregation. Ausgehend von PEG-OPBA-Copolymeren wird gezeigt, wie sich über kontrolliert radikalische Polymerisation responsive Triblöcke herstellen lassen. Das Verhalten dieser Triblöcke in wässriger Lösung wird eingehender untersucht und anhand von Lichstreu- und RKM-Untersuchungen ein Modell entwickelt, welches dieses Verhalten beschreibt. Neben den OPBA beschäftigt sich die Arbeit mit der Synthese wohldefinierter Oligo-p-phenylen-terephthalamide (OPTA). Der Aufbau PEG-basierter Stab-Knäuel-Copolymere mit monodispersem OPTA-Block wird beschrieben und ihre Aggregate mittels RKM dargestellt. Die Copolymere werden verwendet, um verbesserte Haftungseigenschaften an Twaron-Fasern gegenüber reinem PEG zu demonstrieren.

Interplay of pi–pi stacking and hydrogen bonding in conjugated supramolecular systems studied by solid-state NMR

In this work supramolecular organic systems based on rigid pi-conjugated building blocks and flexible side chains were studied via solid-state NMR spectroscopy. Specifically, these studies focussed on phenylene ethynylene based macrocycles, polymer systems including polythiophenes, and rod-coil copolymers of oligo(p-benzamide) and poly(ethylene glycol). All systems were studied in terms of the local order and mobility. The central topic of this dissertation was to elucidate the role of the flexible side chains in interplay of different non-covalent interactions, like pi-pi-stacking and hydrogen bonding.Combining the results of this work, it can be concluded that the ratio of the rigid block and the attached alkyl side chains can be crucial for the design of an ordered pi-conjugated supramolecular system. Through alkyl side chains, it is also possible to introduce liquid-crystalline phases in the system, which can foster the local order of the system. Moreover in the studied system longer, unbranched alkyl side chains are better suited to stabilize the corresponding aggregation than shorter, branched ones.The combination of non-covalent interactions such as pi-pi-stacking and hydrogen bonding play an important role for structure formation. However, the effect of pi-pi-stacking interaction is much weaker than the effect of hydrogen bonding and is only observed in systems with a suitable local order. Hence, they are often not strong enough to control the local order. In contrast, hydrogen bonds predominantly influence the structural organization and packing. In comparison the size of the alkyl side chains is only of minor importance. The suppression of certain hydrogen bonds can lead to completely different structures and can induce a specific aggregation behavior. Thus, for the design of a supramolecular ordered system the presence of hydrogen bonding efficiently stabilizes the corresponding structure, but the ratio of hydrogen bond forming groups should be kept low to be able to influence the structure selectively.