03 Fakultät Chemie

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    Impact of remote mutations on metallo-beta-lactamase substrate specificity : implications for the evolution of antibiotic resistance
    (2005) Ölschläger, Peter; Mayo, Stephen L.; Pleiss, Jürgen
    Metallo-beta-lactamases have raised concerns due to their ability to hydrolyze a broad spectrum of beta-lactam antibiotics. The G262S point mutation distinguishing the metallo-beta-lactamase IMP 1 from IMP 6 has no effect on the hydrolysis of the drugs cephalothin and cefotaxime, but significantly improves catalytic efficiency toward cephaloridine, ceftazidime, benzylpenicillin, ampicillin, and imipenem. This change in specificity occurs even though residue 262 is remote from the active site. We investigated the substrate specificities of five other point mutants resulting from single nucleotide substitutions at positions near residue 262: G262A, G262V, S121G, F218Y and F218I. The results suggest two types of substrates: type I (nitrocefin, cephalothin and cefotaxime), which are converted equally well by IMP-6, IMP-1, and G262A, but even more efficiently by the other mutants, and type II (ceftazidime, benzylpenicillin, ampicillin, and imipenem), which are hydrolyzed much less efficiently by all the mutants, with IMP-1 being the most active. G262V, S121G, F218Y, and F218I improve conversion of type I substrates, whereas G262A and IMP-1 improve conversion of type II substrates, indicating two distinct evolutionary adaptations from IMP-6. Substrate structure may explain the catalytic efficiencies observed. Type I substrates have R2 electron donors, which may stabilize the substrate intermediate in the binding pocket and lead to enhanced activity. In contrast, the absence of these stabilizing interactions with type II substrates may result in poor conversion and increased sensitivity to mutations. This observation may assist future drug design. As the G262A and F218Y mutants confer effective resistance to Escherichia coli BL21(DE3) cells (high minimal inhibitory concentrations), they are likely to evolve naturally.
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    On attempts at solvolytic generation of aryl cations
    (1976) Subramanian, Lakshminarayanapuram R.; Hanack, Michael; Chang, Lawrence W. K.; Imhoff, Michael A.; Schleyer, Paul v. R.; Effenberger, Franz; Kurtz, Walter; Stang, Peter; Dueber, Thomas E.
    The solvolysis of phenyl triflate (3), phenyl nonaflate (4), o-methylphenyl nonaflate (5), o-cyclopropylphenyl nonaflate (6), o-methoxyphenyl triflate (7), 2,6-dimethoxyphenyl triflate (S), 2,6-diisopropylphenyl triflate (9), 33- dimethoxyphenyl triflate (lo), 3,5-dicyclopropylphenyl triflate (11), 3,5-di(2-methylcyclopropyl)phenyl triflate (12), 2,4,6-tricyclopropylphenyltr iflate (13), and 2,4,6-triisopropylphenytlr iflate (14) were examined in great detail under a wide variety of conditions. In highly polar nonnucleophilic solvents no reaction was observed and the unreacted triflates were recovered quantitatively. In the presence of nucleophiles or nucleophilic solvents the sole products observed were the corresponding phenols. Careful labeling and product studies showed that these phenols arose by nucleophilic attack on sulfur and S-0 bond cleavage. We have not been able to find any evidence for aryl cation intermediates.
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    Properties of amphiphilic terminally substituted conjugated nonaene- and 2-docosylnonaene carboxylic acids in monolayers at the air-water interface
    (1991) Effenberger, Franz; Meller, Paul; Ringsdorf, Helmut; Schlosser, Hubert
    In the present communication, we report thesynthesis of conjugated nonaene- and 2-docosylnonaene carboxylic acids with different terminal substituents. These substituents have been chosen so that their spectroscopic properties differ from those of the polyene chain; they also have specific electron donor, electron acceptor or redox properties to allow for specific and selective excitation (energy intake). Because of the amphiphilic character of these compounds, pressure-area isotherms were determined in monolayers at the air-water interface.
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    A novel synthetic route to L-proline (Amino acids ; 7)
    (1986) Drauz, Karl-Heinz; Kleemann, Axel; Martens, Jürgen; Scherberich, Paul; Effenberger, Franz
    Reaction of L-5-oxoproline esters L-2 with phosgene at 0° C gives L-5,51-dichloro-1-(chlorocarbonyl)proliene esters L-6 ,which readily lose hydrogen chloride to form L-5-chloro-1-(chloroarbonyl)-4,5-dehydroproline esters L-7. Catalytic hydrogenation (Pd/C, 180 bar) of L-7 yields L-1-(chlorocarbonyl)proline esters L-15 and thence, upon hydrolysis, L-proline ( L17 ). A "one-pot reaction" for the whole sequence is described, starting from easily accessible L-5-oxoproline esters and yielding L-proline in 78% overall yield and 99.7% optical purity.
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    Experimental and theoretical aspects of the formation of radical cations from tripyrrolidinobenzenes and their follow-up reactions
    (1990) Effenberger, Franz; Stohrer, Wolf-Dieter; Mack, Karl Ernst; Reisinger, Friedrich; Seufert, Walter; Kramer, Horst E.A.; Föll, Rudolf; Vogelmann, Ekehardt
    Tripyrrolidinobenzene radical cations(1*+), obtained from the corresponding arenes by oxidation with silver nitrate, are specially stabilized and thus allow specific reaction pathways of arene radical cations to be investigated separately and individually. Radical cations 1*+ ,for instance, generated under exclusion of oxygen, undergo dimerization to 2, or they abstract hydrogen from the solvent to form 3. In a pure oxygen atmosphere, the O2 reaction products 6 and 7 are formed, respectively, either exclusively or together with 2 and 3. Kinetic measurements give the following order of reactivity for these individual processes: reaction with O2 > dimerization. > H-abstraction from solvent. The changes in the product spectrum upon modification of the reaction conditions are in accord with the kinetic results. The dimeric u complexes 2 show surprisingly facile dissociation into two radical cations, two (1*+)with a much higher dissociation rate for the alkyl derivatives 2b-d than for 2a. Dissociation is enhanced substantially by light or in the presence of π donors. Individual product formation, rate of reactions of the radical cations 1*+, and photochemical cleavage of the dimeric σ complexes 2 can be rationalized, by qualitative and quantitative MO considerations, in terms of their relative frontier orbital energies.
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    Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells
    (2014) Nunna, Suneetha; Reinhardt, Richard; Ragozin, Sergey; Jeltsch, Albert
    The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4–8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60–80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers.
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    Microbial P450 enzymes in biotechnology
    (2004) Urlacher, Vlada B.; Lutz-Wahl, Sabine; Schmid, Rolf D.
    Oxidations are key reactions in chemical syntheses. Biooxidations using fermentation processes have already conquered some niches in industrial oxidation processes, since they allow the introduction of oxygen even into non-activated carbon atoms in a sterically and optically selective manner which is difficult or impossible to achieve by synthetic organic chemistry. Biooxidation using isolated enzymes is limited to oxidases and dehydrogenases. Surprisingly, cytochrome P450 monooxygenases (CYPs) have scarcely been studied for use in biooxidations, although they are one of the largest known superfamilies of enzyme proteins. Their gene sequences have been identified in various organisms such as humans, bacteria, algae, fungi and plants. The reactions catalyzed by P450s are quite diverse and range from biosynthetic pathways (e.g. those of animal hormones and secondary plant metabolites) to the activation or biodegradation of hydrophobic xenobiotic compounds (e. g. those of various drugs in the liver of higher animals). From a practical point of view, the great potential of P450s is limited by their functional complexity, low activity, and limited stability. In addition, P450-catalyzed reactions require a constant supply of NAD(P)H which makes continuous cell-free processes very expensive. Quite recently, several groups have started to investigate cost-efficient ways which could allow the continuous supply of electrons to the heme iron. These include, for example, the use of electron mediators, direct electron supply from electrodes and enzymatic approaches. In addition, methods of protein design and directed evolution have been applied in an attempt to enhance the activity of the enzymes and improve their selectivity. The promising application of bacterial P450s as catalyzing agents in biocatalytic reactions and recent progress made in this field are covered in this review.
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    Über die Reaktion von 2,2-Dimethylpropylidinphosphan mit Wolframhexachlorid : die Kristallstrukturen von [(Cl3PO)WCl4(H9C4-C≡C-C4H9)] und [(H5C6)4As][WCl6]
    (1983) Uhl, Gudrun; Hey, Evamarie; Becker, Gerd; Weller, Frank; Dehnicke, Kurt
    Die Reaktion von 2,2-Dimethylpropylidinphosphan, (CH3)3C-C ≡P|, mit Wolframhexachlorid als Suspension in POCl 3 führt unter Oxydation des Phosphors zu 2,2,5,5-Tetramethylhex-3-in, das mit zugleich entstandenem Wolframtetrachlorid den durch POCl 3 solvatisierten, dunkelgrünen Alkinkomplex [(Cl3PO)WCl4(HgC4-C≡C-C4Hg)] bildet. Ein Teil des Wolframhexachlorids wird nur zu Wolframpentachlorid reduziert und kann nach Zugabe von Tetraphenylarsoniumchlorid als [(H5C6)4As][WCl6] isoliert werden. Für diese Verbindung wird eine neue, sehr einfache Synthese aus WCl6, [(H5C6)4As]Cl und C2Cl4 als Reduktionsmittel beschrieben.Die Struktur von [(Cl3PO)WCl4(H9C4-C≡C-C4H9)] wurde mit Hilfe von Röntgenbeugungsdaten ermittelt (R = 5,8%). Der Komplex kristallisiert monoklin in der Raumgruppe P21/n mit: {a = 1510; b = 1517; c = 849 pm; β 93,1°, Z = 4}. Das Wolframatom ist durch vier äquatorial angeordnete Chloratome, durch die C°C-Gruppe des Acetylen-Liganden und in trans-Position hierzu durch das Sauerstoffatom des POCl3-Moleküls siebenfach koordiniert. Der fast symmetrisch gebundene, voluminöse Acetylenligand drückt die Chloratome in Richtung auf das solvatisierte POCl3-Molekül weg, so daß keine gemeinsame Ebene mit dem Wolframatom möglich ist. Die C°C-Bindungslänge des 2,2,5,5-Tetramethylhex-3-in-Liganden entspricht mit 130 pm dem für eine C°C-Doppelbindung typischen Wert.Das IR-Spektrum von [(H5C6)4As][WCl6] läßt zwei WCl6-Valenzschwingungen erkennen und beweist damit die Verzerrung des regulären Oktaeders. Nach der Kristallstrukturbestimmung (Raumgruppe P4/n; a = 1301; c = 780 pm; Z = 2; R = 2,7%) besitzt das [WCl6]−-Ion annähernd C4V-Symmetrie mit etwas kürzeren W-Cl-Bindungslängen entlang der vierzähligen Drehachse.
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    Whisker formation on Sn thin films
    (2010) Sobiech, Matthias Lukas; Mittemeijer, Eric Jan (Prof. Dr. Ir.)
    The system Sn on Cu will usually be applied for interconnection of modern electronic systems, i.e. for mechanical, thermal and electrical “integration” of electronic components (e.g. composed of Cu) on rigid substrates (i.e. printed circuit boards) by (e.g. Sn) solder-joint technology. Nowadays Sn is the material of choice for this purpose because the up to now commonly and successfully used SnPb alloys for soldering and coating applications are prohibited by law since 1st July 2006 due to environmental concerns (Pb-free and “green” legislation). However, it is well known since nearly 60 years that pure Sn thin films deposited on Cu substrates are very prone to spontaneous formation of needle-like Sn single-crystals, called whiskers, during ageing at room temperature. Such filamentary Sn whiskers exhibiting growth rates of about 1 Å/sec constitute an issue of great technological relevance for Sn coated leadframe legs of modern microelectronic devices because whisker-induced short-circuit failures of various electronic devices have resulted in enormous financial damage including breakdowns of satellites, computer centres and military and medical devices. Unfortunately, profound knowledge on this controversially discussed phenomenon of whisker-growth is still lacking. Therefore, particularly in recent years, the electronic industry promotes scientific activities to arrive at fundamental understanding of Sn whisker formation in order to implement industrially reliable (accelerated) whisker tests and/or mitigation strategies. Against the above background, the present thesis focuses in particular on revealing the driving force for Sn whiskering in the system Sn on Cu during room temperature ageing and thus to devise a coherent understanding of the processes leading to the formation and growth of Sn whiskers. The obtained fundamental interrelations of microstructural evolution, phase formation, residual stress development and the associated whiskering of Sn thin films electro- and sputter-deposited on Cu as well as of SnPb thin films electrodeposited on Cu during ageing at room temperature have lead to a qualitative understanding of whisker growth in terms of localized Coble-creep. On this basis, whisker mitigation strategies can be proposed.
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    Molekül- und Kristallstruktur des Methyl[(N-phenyl,N-trimethylsilyl)thiocarbamoyl]trimethylsilylphosphans (Acyl- und Alkylidenphosphane ; 27)
    (1985) Becker, Gerd; Massa, Werner; Schmidt, Roland E.; Uhl, Gudrun
    Das durch Addition von Methylbis(trimethylsilyl)phosphan an Phenylisothiocyanat gebildete [1] Methyl[(N-phenyl,N-trimethylsilyl)thiocarbamoyl]trimethylsilylphosphan 1a kristallisiert monoklin in der zentrosymmetrischen Raumgruppe P21/n mit folgenden, bei einer Meßtemperatur von -80 ± 3°C bestimmten Abmessungen der Elementarzelle: a=1041,2(4); b=1706,9(12); c=1001,1(6) pm; β-106,41(4)°; Z = 4. Die Röntgenstrukturanalyse (Rw = 0,039) bestätigt die bereits aus den NMR-Spektren abgeleitete Konstitution der Verbindung mit an Phosphor- und sp2-hybridisiertes Stickstoffatom gebundenen Trimethylsilyl-Gruppen. Charakteristische gerundete Bindungslängen und -winkel sind: P-Si 231, P-CH3 184, P-C(S) 187, C=S 167, N-C(S) 137 und N-Si 181pm sowie P-C-S 122°, P-C-N 117° und S-C-N 121°.