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Ras proteins, most notably isoform KRas4B are frequently mutated oncogenes in numerous human cancers and associated with poor prognosis. Despite ambitious research affords since the discovery of Ras proteins as human oncogenes in 1982, no pharmacological therapy approach reached the clinic yet and Ras is still viewed as “undruggable” protein. For signal propagation, Ras proteins have to be localized at the plasma membrane. Enrichment there is facilitated by spatial cycles that utilize the pre...
The reaction of sodium chloride with 2-[bis(2-hydroxyethyl)amino]ethan-1-ol results in the formation of the title salt {[Na{N(CH2CH2OH)3}]Cl}n. The polymeric structure is characterized by a sodium cation coordinated by one nitrogen and five oxygen atoms in a distorted octahedral environment. The resulting one-dimensional {—O—Na—O—Na—O}— coordination polymer extends parallel to [010] and is connected through the chloride counter-anion via O—H...Cl hydrogen bonding, giving rise to a two-...
Protein ligand interaction fingerprints are a powerful approach for the analysis and assessment of docking poses to improve docking performance in virtual screening. In this study, a novel interaction fingerprint approach (PADIF, protein per atom score contributions derived interaction fingerprint) is presented which was specifically designed for utilising the GOLD scoring functions’ atom contributions together with a specific scoring scheme. This allows the incorporation of known protein–lig...
The title compound, C18H22, is a coupling product of two metallated mesitylene molecules. The dihedral angle between the aromatic rings is 11.10 (5)° and the Car—Cm—Cm—Car (ar = aromatic and m = methylene) torsion angle is 179.60 (14)°. No directional interactions beyond normal van der Waals contacts could be identified in the crystal. To our best knowledge, it is the first known coupling product of metallated mesitylene.
Self-assembled, porous coordination cages with a functional interior find application in controlled guest inclusion/release, drug delivery, separation processes, and catalysis. However, only few studies exist that describe their utilization for the development of self-assembled materials based on their 3-dimensional shape and external functionalization. Here, dodecyl chain-containing, acridone-based ligands (LA) and shape-complementary phenanthrene-derived ligands (LB) are shown to self-assem...
Porous nanostructures and materials based on metal-mediated self-assembly have developed into a vibrantly studied subdiscipline of supramolecular chemistry during the past decades. In principle, two branches of such coordination compounds can be distinguished: Metal–organic frameworks (MOFs) on the one side represent infinite porous networks of metals or metal clusters that are connected via organic ligands to give solid-state materials. On the other hand, metal–organic cages (MOCs) are discr...
In dieser Arbeit lag der Fokus auf der Entwicklung und Untersuchung von Mikroschwimmern auf Basis der Marangoni-Konvektion. Das Ziel bestand in dem Verständnis des Systems und darin verschiedene Ein ussparameter aus ndig zu machen um das System zu optimieren. Außerdem sollten durch Untersuchungen mit vielen Mikroschwimmern ein erster Einblicke in das komplexe Schwarmverhalten der Mikroschwimmer erhalten werden. Hierzu war es unerlässlich, zunächst eine geeignete Methode zur Verfolgung de...
Die Synthese von Naturstoffen ist seit fast 200 Jahren eine Kerndisziplin der organischen Chemie. Dabei bieten komplexe natürliche Moleküle immer neue Herausforderungen für Chemiker und verlangen dadurch neue Lösungen. Besonders marine (Mikro-)Organismen haben sich als eine ergiebige Quelle verschiedenster chemisch wie auch biologisch interessanter Naturstoffe erwiesen. Die vorliegende Arbeit behandelt hauptsächlich die Totalsynthese von Belizentrin Methylester. Die Stammverbindung Beli...
Die Enzyme Acyl Protein Thioesterase 1 und 2 (APT1 und APT2) spielen eine wichtige Rolle bei der Depalmitoylierung verschiedener Protein in der Zelle, unter anderem deacylieren sie das Protoonkogen Ras. Damit verhindern sie die fehlerhafte Lokalisierung von Ras an internen Membranen, was die Signalweiterleitung von extraellulären Botenstoffen durch das Ras Protein an der Plasmamembran ermöglicht. Die Repalmitoylierung von Ras erfolgt am Golgi-Apparat. Die Inhibierung von APT kann diesen Zyklu...
Letztendlich ist alles Leben Nichtgleichgewichtsthermodynamik und beruht auf einem korrekten Zusammenspiel der Struktur und Dynamik biologischer Makromoleküle. Gegenstand dieser Arbeit ist die Fragestellung, inwieweit Struktur, Dynamik und damit auch die Funktionalität von Proteinen und Modellmembranen sich gegenseitig beeinflussen und durch Druckapplikation und Zugabe von Osmolyten, und somit durch Änderungen der Lösungsbedingungen, modifiziert werden können. Leben ist unter diversen extrem...
Photochromic [Pd2L4] coordination cages based on dithienylethene (DTE) ligands L allow triggering guest uptake and release by irradiation with light of different wavelengths. The process involves four consecutive electrocyclic reactions to convert all chromophores between their open and closed photoisomeric forms. So far, guest affinity of the fully switched species was elucidated, but mechanistic details concerning the intermediate steps remained elusive. Now, a new member of the DTE cage fa...
Proteins of the Ras family of small GTPases play a major role in the transduction of extracellular signals, especially growth factor signals, into the cell. Ras proteins thereby participate in the regulation of critical processes like cellular growth and proliferation. Due to this central role, gain-of-function mutations of these proteins can have severe consequences for the mutated cells including uncontrolled proliferation and these mutations are often connected to development of diseases i...
Im Jahr 2010 berichteten Rho et al. von der Isolierung, Strukturaufklärung und biologischen Evaluierung des Tetraterpenoids Gukulenin A aus dem marinen Schwamm Phorbas gukhulensis. Neben faszinierenden strukturellen Merkmalen, wie einem einzigartigen pseudodimeren Terpengrundgerüst sowie hochsubstituierten α-Tropoloneinheiten, zeigt Gukulenin A eine bemerkenswerte Cytotoxizität gegenüber unterschiedlichen menschlichen Krebszelllinien. Die vorliegende Arbeit beschreibt die Ausarbeitung einer...
The development of novel and efficient methods for the transition metal-free functionalization of inert and abundant C–H bonds offers striking advantages in terms of step- and atom economy under environmentally benign reaction conditions. Metal-free reactions serve as environmentally friendly substitutes for cost intensive and harmful transition metal-catalyzed reactions. However, oxidative coupling reactions under metal-free conditions face some unsolved problems. High molecular weight oxida...
(Aminomethyl)ferrocene stellen eine wichtige Verbindungsklasse in Hinblick auf neuartige chirale Liganden dar und haben ihr chemisches Potential bei weitem noch nicht ausgeschöpft. Als Resultat der vorliegenden Arbeit können abhängig von Reaktionsbedingungen und zuvor eingeführten Substituenten selektiv unterschiedliche Positionen an beiden Ferrocenylringen angesteuert werden. Das enantiomerenreine ortho-lithiierte (Aminomethyl)ferrocen, zugänglich durch asymmetrische Metallierung, ist die S...
The technological development in analytical methods, especially in chromatography and mass spectrometry, has allowed a deeper understanding of biological systems at a molecular level. Characterization and quantification of biomolecules and its modifications are crucial for comprehension of the entire biological machinery. However, additional bioanalytical methods are needed to gain more detailed information about protein structure, dynamic protein complexes and low abundant protein modificati...
Genetic information within a cell is stored in the nucleotide sequence of deoxyribonucleic acid (DNA). In a multicellular organism, all somatic cells contain the same genetic material i.e. have the same genotype. Nevertheless, they can differ greatly in their morphologies and functions, which is commonly attributed to a differentiated pattern of gene expression. Responsible for the formation of a cell´s specific phenotype are epigenetic modifications, which act as an additional layer of i...
The Hedgehog (Hh) signaling pathway is vital for organ development and tissue patterning during embryogenesis. However, its inappropriate activation is linked to several types of cancers. Therefore, development of small molecule modulators of Hh pathway is of utmost importance in the field of cancer research. A high-throughput cell-based screen in C3H/10T1/2 cells that monitor osteogenesis upon activation of Hh signaling identified YCL-220, RKN-1043 and MJD-1314 as inhibitors of Hh signalin...
Herein, the first concise total synthesis of belizentrin methyl ester as a stable derivative of the natural product is described. Belizentrin was isolated as a structurally complex secondary metabolite from the marine dinoflagellate Prorocentrum belizeanum. This polyketide is a potent neurotoxin decorated with 16 stereocentres in total, comprising of a polyunsaturated macrocyclic core structure and a polyhydroxylated sugar-based sidechain. Key steps of the synthesis of the western polyhyd...
A donor‐site engineering approach facilitates the formation of heteroleptic [Pd2L2L′2]4+ cage structures through a favored cis‐′in2/out2′ spatial configuration of the methyl groups of 5‐ and 3‐substituted bis‐monodentate picolyl ligands with flat acridone and bent phenothiazine backbones. The heteroleptic cages were confirmed by ESI‐MS and 2D NMR experiments as well as DFT calculations, which pointed toward a cis‐configuration being energetically favored. This was further supported by the syn...