Neodymmischmetall-Hydrid

[No abstract available

Chemische Synthese und Evaluierung von 2'3'-cGAMP-Analoga

Der second messenger 2‘3‘-cGAMP besteht aus einer außergewöhnlich verknüpften Adenosin- und Guanosinmonophosphat Einheit. Eine nicht-kanonische 2’-5’- und eine kanonische 3‘-5‘-Phosphodiesterbindung bilden den 13-gliedrigen Makrozyklus. Innerhalb der Zelle nimmt dieses zyklische Dinukleotid eine entscheidende Schlüsselfunktion ein, um die angeborene Immunantwort über die cGAS-STING-Achse zu steuern. Diese Signalkaskade wird durch das Auftreten von doppelsträngiger DNA im Zytosol ausgelöst, z.B. während Infektionen oder Zell-Gleichgewichtsstörungen. Dem Immunotransmitter 2‘3‘-cGAMP wird ein immenses therapeutisches Potenzial attestiert, um die cGAS-STING-Achse in Immunzellen zu modulieren. Denn es besteht die Hoffnung, dass degenerierte Zellen eines Organismus selektiv und schonend aussortiert werden können (z.B. bei Krebszellen) – anders als bei Chemotherapien, die mit starken Nebenwirkungen verbunden sind. Die pharmakokinetischen Eigenschaften von 2‘3‘-cGAMP sind allerdings nicht ausreichend, um die Anforderungen eines potenten Arzneimittels zu erfüllen. Grund dafür ist unter anderem die Natur der zwei negativ geladenen Phosphodiesterbindungen und der damit einhergehenden schlechten Penetration der Zellmembran. In der vorliegenden Dissertation wurde ein neutral geladenes 2‘3‘-cGAMP-Analogon über 20 Stufen im 100 mg-Maßstab synthetisiert mit mutmaßlich verbesserter Membranpermeation. Der Zyklus wurde durch einen Triazol- und Amid-Linker verbrückt. Dadurch wurde ein synthetischer Zugang zu neutralen Nukleosid-Cyclophanen geschaffen. Eine Ligandenbindung mit STING konnte nicht detektiert werden und die inhibitorischen Effekte auf cGAS besaßen in vitro Optimierungsbedarf. In einem weiteren Ansatz wurde ein fluoreszierendes Analogon mit einer modifizierten Thiophen-Nukleobase in 11 Stufen konstruiert. Dieses sollte das Studium der STING-Mikroumgebung in Abhängigkeit der Fluoreszenzintensität, neue Ligandenverdrängungsassays oder bildgebende Mikroskopieverfahren ermöglichen. Während das sogenannte 2‘3‘-TorGAMP an murines STING eine nanomolare Bindung zeigte, erforderten die Bindungsinteraktionen mit humanem STING noch strukturelle Weiterentwicklungen (mikromolare Bindung). Mit den unten dargestellten cGAMP-Analoga konnten die sensiblen STING-Interaktionen untersucht werden.The second messenger 2‘3‘-cGAMP consists of an unusually connected adenosine and guanosine monophosphate unit. The 13-membered macrocylce is composed of a non-canonical 2‘-5‘ and a canonical 3‘-5‘ phosphodiester bond. Within the cell, this cyclic dinucleotide holds key functions by controlling the innate immune response via the cGAS-STING axis. During infections or disruptions of the cell’s homeostasis the cGAS-STING signaling cascade is triggered by the occurrence of double stranded DNA in the cytosol. It is believed that the immunotransmitter 2’3’-cGAMP possesses remarkable therapeutic potentials because it is able to tune the cGAS-STING pathway in immune cells. On account of this, there is hope to eliminate degenerated cells under selective and mild conditions (e.g. cancer cells) – in contrast to chemotherapies which feature severe side effects. The pharmakokinetic properties of 2‘3‘-cGAMP, however, are not sufficient to meet the requirements of a potent and modern drug. One of the reasons are the two negatively charged phosphodiester bridges and their resulting poor penetrability of the cell membrane. Here, a neutrally charged 2’3’-cGAMP analogue was synthesized on a 100 mg scale over 20 steps with potentially better membrane crossing characteristics. The cycle was linked by a triazol- and amide connection which now provides synthetic access to neutral nucleoside cyclophanes. Further studies of the binding affinity to STING revealed no detectable binding of the ligand. The potential inhibitory effects towards cGAS in vitro require optimization. A second part of this thesis was devoted to the 11-step-synthesis of a fluorescent 2’3’-cGAMP analogue containing a modified thiophen nucleobase. The fluorescent molecule was prepared in order to probe the STING microenvironment and for the development of a new ligand competition assay with the help of new cell imaging methods. While the so-called 2‘3‘-TorGAMP bound to murine STING in nanomolar affinity, the binding interactions with human STING still required structural modifications (micromolar binding). With these two cGAMP analogues in hand, the sensitive STING binding modes could be examined

Blue Emitting SrBe1−xSi2+xO3−2xN2+2x:Eu2+ (x≈0.1)

In the search for materials for high-efficiency lighting applications, the color-point tuning of phosphors for inorganic phosphor converted LEDs (pcLEDs) is of special interest. We expand the recently explored phosphor class of SiBeONs (oxonitridoberyllosilicates) by the synthesis and characterization of SrBe1−xSi2+xO3−2xN2+2x:Eu2+. High temperature synthesis, starting from Sr2N, BeO, SiO2 and Si3N4, yields the target phase as the main product. Upon doping with Eu2+, the pale blue crystals exhibit blue luminescence with emission at 456 nm and a full width at half maximum (fwhm) of 66 nm/3108 cm−1. The structure is an ordered variant of the LaSi3N5 structure type and was elucidated by single-crystal X-ray diffraction data. The network in SrBe1−xSi2+xO3−2xN2+2x:Eu2+ is highly condensed with a condensation degree of κ=0.6 comprising corner-sharing [MX4] (M=Be, Si; X=O, N) tetrahedra, with mixed occupancies on both the ligand and central metal sites

Datenbasiertes kommunales Bildungsmanagement nachhaltig verankern

DATENBASIERTES KOMMUNALES BILDUNGSMANAGEMENT NACHHALTIG VERANKERN Datenbasiertes kommunales Bildungsmanagement nachhaltig verankern / Dialer, Carmen (Rights reserved) ( -

Order and Disorder in Mixed (Si, P)–N Networks Sr2SiP2N6:Eu2+ and Sr5Si2P6N16:Eu2+

In the field of nitride phosphors, which are crucial for phosphor-converted light-emitting diodes, mixed tetrahedral networks hold a significant position. With respect to the wide range of compositions, the largely unexplored (Si, P)–N networks are investigated as potential host structures. In this work, two highly condensed structures, namely Sr2SiP2N6 and Sr5Si2P6N16 are reported to address the challenges that arise from the similarities of the network-forming cations Si4+ and P5+ in terms of charge, ionic radius, and atomic scattering factor, a multistep workflow is employed to elucidate their structure. Using single-crystal X-ray diffraction, energy-dispersive X-ray spectroscopy (EDX), atomic-resolution scanning transmission electron microscopy (STEM)-EDX maps, and straightforward crystallographic calculations, it is found that Sr2SiP2N6 is the first ordered, and Sr5Si2P6N16 the first disordered, anionic tetrahedral (Si, P)–N network. After doping with Eu2+, Sr2SiP2N6:Eu2+ shows narrow cyan emission (λmax = 506 nm, fwhm = 60 nm/2311 cm−1), while for Sr5Si2P6N16:Eu2+ a broad emission with three maxima at 534, 662, and 745 nm upon irradiation with ultraviolet light is observed. An assignment of Sr sites as probable positions for Eu2+ and their relation to the emission bands of Sr5Si2P6N16:Eu2+ is discussed

Chemical Synthesis of the Fluorescent, Cyclic Dinucleotides c(th)GAMP

The cGAS-STING pathway is known for its role in sensing cytosolic DNA introduced by a viral infection, bacterial invasion or tumorigenesis. Free DNA is recognized by the cyclic GMP-AMP synthase (cGAS) catalyzing the production of 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP) in mammals. This cyclic dinucleotide acts as a second messenger, activating the stimulator of interferon genes (STING) that finally triggers the transcription of interferon genes and inflammatory cytokines. Due to the therapeutic potential of this pathway, both the production and the detection of cGAMP via fluorescent moieties for assay development is of great importance. Here, we introduce the paralleled synthetic access to the intrinsically fluorescent, cyclic dinucleotides 2'3'-c(th)GAMP and 3'3'-c(th)GAMP based on phosphoramidite and phosphate chemistry, adaptable for large scale synthesis. We examine their binding properties to murine and human STING and confirm biological activity including interferon induction by 2'3'-c(th)GAMP in THP-1 monocytes. Two-photon imaging revealed successful cellular uptake of 2'3'-c(th)GAMP in THP-1 cells

A Click-Chemistry Linked 2’3’-cGAMP Analog

2’3’-cGAMP is an uncanonical cyclic dinucleotide where one A and one G base are connected via a 3’-5’ and a unique 2’-5’ linkage. The molecule is produced by the cyclase cGAS in response to cytosolic DNA binding. cGAMP activates STING and hence one of the most powerful pathways of innate immunity. cGAMP analogs with uncharged linkages that feature better cellular penetrability are currently highly desired. Here, we report the synthesis of a cGAMP analog with one amide and one triazole linkage. The molecule is best prepared via a first Cu(I) catalysed click reaction which establishes the triazole, while the cyclization is achieved by macrolactamization

4-[2-(Cyclo­hexa-1,4-dien-1-yl)eth­oxy]benzene-1,2-dicarbonitrile

In the title compound, C16H14N2O, the dihedral angle between the aromatic rings is 70.23 (6)°. The linking chain has a zigzag conformation. In the crystal, mol­ecules are linked by weak inter­molecular C—H⋯N hydrogen bonds, forming a zigzag chain along the c axis

Chiral separation of substituted phenylalanine analogues using chiral palladium phosphine complexes with enantioselective liquid–liquid extraction

Chiral palladium phosphine complexes have been employed in the chiral separation of amino acids and phenylalanine analogues in particular. The use of (S)-xylyl-BINAP as a ligand for the palladium complex in enantioselective liquid–liquid extraction allowed the separation of the phenylalanine analogues with the highest operational selectivity reported to date. 31P NMR, FTIR, FIR, UV-Vis, CD and Raman spectroscopy methods have been applied to gain insight into the binding mechanism of the amino acid substrates with the chiral palladium phosphine complexes. A complexation in a bidentate fashion is proposed.