Techn. Universiẗat, Diss., 2005--München.

Techn. Hochsch., Diss., 2000--Aachen.

No description available.

The review of this thesis describes palladium catalysed allylic amination in the context of the mechanism and synthetic utility. Examples of alkene geometry, regioselectivity and net retention have been illustrated as a consequence of the amination mechanism. The synthetic aspects of palladium catalysed allylic amination consists of other examples of the formation of enantiomerically enriched allylic amines and amino acids.

Phosphines and phosphites have been investigated as ligands to tetraphenylporphinato iron(II) (FeTPP) by spectrophotometric titration in tetrahydrofuran. A least squares method for determination of the equilibrium constants K1 and K2 (K1 and K2 correspond to the sequential binding constants for the formation of FeTPPL and FeTPPL2, respectively) was developed. This method eliminates the errors associated with fundamental assumptions intrinsic to the more conventional Hill plot. The visible spectrum of the 5-coordinate complex, FeTPPL, was also determined for each ligand. The equilibrium constants obtained are: {L(logK1, logK 2)}, PMe3 (5.53, 4.60); PEt3 (5.61, 4.30); P(n- Bu)3 (6.13, 5.02); P(OEt)3 (3.87, 2.82); P(O-i-Pr)3 (3.28, 1.13). The equilibrium constants are dependent upon steric bulk, σ-basicity and π-acidity.

Objectives: Periodontal disease is a chronic inflammation resulting in periodontal attachment loss. Keratinocyte Growth Factor-1 (KGF-1) is upregulated in chronic inflammation and specifically stimulates epithelial cell proliferation by signaling through the epithelial-specific Keratinocyte Growth Factor Receptor (KGFR). First, we examined KGF-1 and KGFR expression and localization in human periodontal tissues. Second, we extended these studies by developing an in vitro mechanical wound model to mimic trauma to the periodontal pocket epithelium and examined ligand independent KGFR activation and cell migration. Methods: In our study of human gingival tissues, we used immunohistochemistry and laser capture microdissection with RT-PCR to analyze KGF-1 and KGFR expression and localization. To study ligand independent KGFR phosphorylation, KGFR internalization along the wound edge was imaged using immunohistochemical staining and KGFR phosphorylation confirmed using immunoprecipitation with western blotting. Wounding induced oxidative stress was detected using DCFH-DA (2',7'-dichlorofluorescin diacetate) and modulated by pretreatment with an antioxidant. Changes in migration were examined in the presence or absence of pathway specific inhibitors. Results: KGF-1 protein localized to areas of junctional and basal oral epithelial cells was significantly increased in periodontal pocket epithelium (p<0.01) and oral epithelium (p<0.05) of disease-associated tissues. KGFR localized to the junctional and the parabasal cells of oral epithelium, and was increased in disease-associated pocket epithelium (p<0.05). Laser capture microdissection with RT-PCR confirmedKGF-1 and KGFR were specifically expressed by connective tissue and epithelium, respectively. In our cell culture model, mechanical wounding induced ligand independent KGFR activation. ROS (Reactive Oxygen Species) generation along the wound edge was associated with KGFR activation and scavenging of ROS reduced KGFR phosphorylation. The c-Src family inhibitor, PP1, significantly inhibited KGFR phosphorylation. Functionally cell migration was reduced by PP1 (82.7%), SU5402(70%) and PD98059 (57%). Conclusions: KGF-1 and KGFR proteins are expressed in health but significantly induced in human diseased periodontal tissues. Microwounding associated generation of ROS mediates KGFR phosphorylation via c-Src kinase signaling and induced wound edge cell migration. Therefore, regulation of epithelial cell behavior associated with the onset and progression of periodontal disease may possibly be mediated by two related but distinct mechanisms. (1) Ligand-dependent activation of KGFR due to upregulation of KGF-1. (2) Ligand-independent activation of KGFR due to chronic microwounding. / Dentistry, Faculty of / Graduate

A number of iron carbonyl complexes has been prepared from the mixed ligands F₄AsP and F₆AsP and the iron carbonyls Fe(CO)₅ , Fe₂(C0)₉ and Fe₃(C0)₁₂. They are isolated by chromatographic methods and characterized by spectroscopic techniques. These complexes, which can be classified into ten groups, are the only series of iron complexes of organo-bridged mixed ligands known so far. The complex (F₄AsP)₂Fe(CO)₃ is probably the first example of a L₂Fe(CO)₃ compound in which the two polydentate ligand molecules behave as mono-dentates and occupy the two trans positions of a trigonal bipyramidal structure. The isolation of P-bonded complexes F₄AsPFe(CO)₄, F₆AsPFe(CO)₄ and (F₄AsP)₂FeCO)₃ and the complete absence of the corresponding As-bonded complexes clearly illustrate that the PPh₂ group is a better coordinating group than the AsMe₂ⁿ group. The novel complexes LmLFe₂(CO)₅ (Lm = monodentate ligand), LbLFe₂(CO)₄ (Lb = bridging group) and Lc LFe₂(CO)₄ (Lc = chelating group) are derived from the very stable LFe₂(C0)₆ complexes (L = F₄AsP, F₆AsP). The structures of these are unusual in that they contain two types of ligand molecules, one acting as a tri-dentate group while the other acting as a mono-dentate group, a bridging group or a chelating group. It is interesting to note that the F₄AsP forms two complexes of the same molecular formula, namely, (F₄AsP)b F₄AsPFe₂(CO)₄ and (F₄AsP)c F₄AsPFe₂(CO)₄, which can be distinguished by infrared and Mossbauer data. Moreover, two additional complexes of the same molecular formula, (F₄AsP)b F₆AsPFe₂(CO)₄ and (F₆AsP)c F₄AsPFe₂(CO)₄ ՚ are obtained from F₄AsP and F₆AsP The method of preparation and the spectroscopic properties of the mixed ligands and their complexes are discussed. The factors which affect the formation of the iron carbonyl complexes are investigated and the possible reaction mechanisms for their formation are proposed. / Science, Faculty of / Chemistry, Department of / Graduate

An array of carbazole-bis(azole) (CzTR and CzTrR, Cz = carbazole, T = tetrazole, Tr = triazole, R = Me, iPr, Bz and CH2Mes) pincer ligands were synthesized and fully characterized by NMR, X-ray crystallography and high resolution mass spectrometry. The physical properties of these ligands, as well as their applications in metal coordination compounds, were extensively studied. Mono, bis- and tris-ligand lanthanide (Y, Yb, Er, Sm, and Ce) complexes were synthesized and the solid state crystal structures of these complexes revealed the unusual binding modes of these ligands. The capability of these ligands to distort from planarity and bind in a fac type fashion, as well as bidentate, rather than tridentate modes was unexpected. The reactivity of the mono-ligand lanthanide complexes was explored and showed modest activity in ring-opening polymerization of lactones, as well as some unusual one electron redox chemistry. Bis-ligand complexes of some first row transition metals (Fe, Co, Ni and Zn) were also explored. These air-stable complexes proved invaluable in studying the physical properties of the ligands themselves, as well as the metal complexes. The bis-ligand zinc complexes (CzTiPr)2Zn and (CzTriPr)2Zn showed reversible oxidation of the CzT and CzTr ligands at modest potentials, as well as ligand-based fluorescence. Two bis-ligand iron complexes were synthesised using sterically diverse ligands (CzTiPr)2Fe and (CzTCH2Mes)2Fe and while (CzTCH2Mes)2Fe showed temperature-independent paramagnetism, the similar (CzTiPr)2Fe complex showed a two-step thermally induced spin crossover phenomenon near room temperature in the solid state. The oxidation of (CzTiPr)2Fe yielded [(CzTiPr)2Fe]+ BF4-; we have speculated that this complex is initially oxidized at the ligand and then undergoes an electron transfer from the metal to the ligand to result in an Fe(III) complex. Mono-ligand iron complexes using the CzTiPr ligand were also synthesized. While ligand redistribution hindered initial progress, the use of a bulky phenoxide ancillary ligand arrested the redistribution pathway and allowed the synthesis of (CzTiPr)Fe(OAr)(THF). This iron complex proved to be the most successful in terms of isolating stable and reactive complexes with our ligands, and several adducts (THF, tBuNC, TPPO) were synthesized. Synthetic and DFT studies of these complexes demonstrated the tendency for the Fe to bind σ-donor ligands, but not π-acceptor ligands. This led to the isolation of a thermally sensitive four-coordinate iron complex (CzTiPr)Fe(OAr). The catalytic activity of these Fe phenoxide complexes in the hydrosilylation of styrene with phenylsilane was explored. These catalysts were able to selectively produce the Markovnikov hydrosilylation product with good activity. The apparent preservation of the Fe(II) oxidation state throughout the catalytic transformation suggests a possible ligand-assisted mechanism where the CzT ligand acts as a proton reservoir. / Graduate / 2021-11-23

Seit mehr als zwei Jahrzehnten ist bekannt, dass nicht nur der Tumor Nekrose Faktor-α (=TNF-α) sondern auch Lymphotoxin-α (=LTα) in Form von Trimeren an TNFR1 und TNFR2 binden kann. Durch diese Fähigkeit an beide Rezeptoren zu binden, haben diese zwei Liganden eine essentielle Rolle in der Entwicklung und dem Verlauf von Autoimmunerkrankungen. Bereits mit Beginn der 1990er Jahren wurde gezeigt, dass LTα nicht nur in Form von Homotrimeren vorliegt, sondern auch mit dem verwandten TNF-Superfamilie Liganden Lymphotoxin β (=LTβ) Heterotrimere bilden kann. Hierbei lagern sich LTα und LTβ in Form von LTα2β und LTαβ2 zusammen. Die initialen Experimente mit diesen Heterotrimeren zeigten bereits Unterschiede von LTα2β und LTαβ2. Während LTα2β wie LTα an den TNFR1 bindet, kann LTαβ2 weder an TNFR1 noch TNFR2 binden und interagiert mit einem eigenen Rezeptor namens Lymphotoxin β Rezeptor (=LTβR). Da bereits zwei Liganden (TNF und LTα) für TNFR1 und TNFR2 bekannt waren, wurde LTα2β bis heute nicht weiter charakterisiert. LTαβ2 hingegen war lange Zeit der einzige bekannte Ligand für den LTβR, weshalb die LTαβ2-LTβR-Interaktion ausführlich untersucht wurde. Diese Arbeit fokusiert sich auf die Charakterisierung von LTα2β. Hierfür wurde die einzige bekannte Eigenschaft aus den 90er Jahren von LTα2β nämlich die Bindung an TNFR1 aufgegriffen und um die Rezeptoren TNFR2 und LTβR erweitert. Diese Arbeit zeigt, dass LTα2β nicht nur an den TNFR1, sondern auch an TNFR2 und schwach an LTβR bindet. Trotz der asymmetrischen Bindestellen kann membrangebundenes LTα2β TNFR1 und TNFR2 nicht nur binden, sondern ist auch in der Lage diese zu aktivieren. Diese Arbeit gibt erste Einblicke in die Komplexizität dieses Heterotrimers indem gezeigt wird, dass LTα2β sowohl in seiner löslichen als auch in seiner membrangebundenen Form den TNFR1 aktivieren kann, während der TNFR2 nur durch das membranständige LTα2β aktiviert wird. Aufgrund der aktivierenden Eigenschaften von membranständigem LTα2β und LTαβ2 auf die murine (=mu) Panc02-Zelllinie wird ein ersten Ausblick auf mögliche weitergehende Experimente in mausbasierten Modellen gegeben. Die erzielten Ergebnisse zeigen, dass mit membranständigem LTα2β ein neuer TNFR2 Agonist gefunden wurde. / Since more than two decades it is known, that not only the Tumor Necrosis Factor-α (=TNF-α) but also lymphotoxin-a (=LTα) bind to TNFR1 and TNFR2. Because of their ability to interact with both of these two receptors, the two ligands play a crucial role in the development and persistence of autoimmune diseases. Already at the beginning of the 1990th, it has been shown that LTα forms homotrimers but is also able to form heterotrimers with the related TNF-Superfamily ligand lymphotoxin-β (=LTβ). Thereby, LTα and LTβ associate to form LTα2β and LTαβ2. Initial experiments already have shown differences between LTα2β and LTαβ2. While LTα2β can bind to TNFR1 like LTα, LTαβ2 can bind neither to TNFR1 nor to TNFR2 but interacts with its own receptor called LTβR. Due to the fact that already two ligands (LTα and TNF) for TNFR1 and TNFR2 were known, LTα2β was not further characterized. Since LTαβ2 was the only known ligand for the LTβR, this LTαβ2-LTβR interaction was further and intensively investigated. This work is focused on LTα2β and its characterization. For this purpose the initial and only finding reported for in the 1990th namely the binding to TNFR1 were taken up and expanded for the interaktion with TNFR2 and LTβR. The results of this work show that LTα2β can not only bind to TNFR1, but also to TNFR2 and weaker to LTβR. Despite its asymmetric binding sites, membrane bound LTα2β was shown not only to bind, but also to be able to activate TNFR1 and TNFR2. This work shows that LTα2β can activate the TNFR1 receptor in its soluble and membrane bound form while TNFR2 can only be activated by membrane bound LTα2β. Due to the activating properties of membrane bound LTα2β and LTαβ2 on murine (=mu) Panc02 cells a first outlook on further experiments in mouse based models will be given. These findings show, that membrane bound LTα2β is a new TNFR2 agonist.

This work focuses on pigmy sperm whale and horse myoglobins (Mbs), which are distinguished by a single heme pocket residue variant in the CD3 position, when the heme iron is in the +3 oxidation state (i.e. the met form). The strategy employed is as follows: (i) assign heme peripheral protons; (ii) assign the amino acid residues from the heme cavity; (iii) assess the dynamics of ligand binding in the active site by means of hydrogen Iability, solvent isotope effects, and heme-insertion isomer trapping, all by NMR methods. The results of these studies portray dynamic solution structure of the Mb ligand binding site, and provide a set of standard parameters for the studies of larger hemoproteins. The findings are also important for understanding protein-ligand interactions in general. My research investigates the mixed spin metazido and metimidazole complexes of Mbs for the following reasons. First, the allosteric properties of hemoglobin arise mainly from the transition between its two possible quaternary structures. This can be studied by paramagnetic NMR because it is one of the most sensitive tools in terms of changes in the molecular and/or electronic structure of the heme. Second, both the N₃- and imidazole (lm-) complexes are good compromises, in terms of sizes, between the small diatomic oxygen or CN⁻ molecules and the bulky phenyl group. Thus, we can determine the influence of ligand size on structural perturbation of the Heme crevice by comparison among the different size groups. Third, the saturation-transfer phenomenon between metMbIm and metMbH₂0 provides a route to assignments in metMbH₂0 by using assignments of metMbIm. This is crucial because metMbH₂0 is the basis of theoretical calculations of the isotropic shift due to axial ligand field in pure high-spin hemoproteins. Finally, the importance of the metMbIm is underscored by the fact that it is a bis-imidazolium complex, which can then serve as a model other bis-histidyl proteins. Most of the heme peripheral resonances of metEqMbIm and metEqMbN₃ were identified by means of two-dimensional NOESY,COSY, and EXSY spectroscopy. The strongly relaxed upfield protons in metMbIm were assigned based on steady-state 1D NOE and T₁ experiments. Based on the results from metMblm in which saturation transfer of one upfield resonance led to two different free ligand peaks, bound Im equilibration was envisioned and proven by the divergence of broad downfield heme methyl peaks into two peaks each, showing distinctive population preference of each isomer. Dicyanoheme probe, as well as hydrogen Iability comparison studies between pigmy sperm whale Mb and horse Mb in the azido and imidazole states, asserts that single variant pocket residue CD3 is crucial in gating the ligand mobility into and out of the active site. The assignments of heme peripheral and upfield resonances enabled the subsequent assignments of some heme pocket amino acid residues. The facile exchange of bound Im with solvent H₂0 lays the ground work for identification of heme pocket residues in metMbH₂0. Furthermore, while deuterated heme previously allowed only assignment of the non-diastereomeric specific heme 2-vinyl β proton, saturation-transfer from horse imidazole Mb affords the specific identification of 2Hᵦt.