Photomonomers and Photoinitiators for Light-Induced Polymerizations in Metal-Organic Frameworks

Die vorliegende Doktorarbeit beschreibt die Synthese von Initiatoren und Monomeren für licht-induzierte Polymerisationen in (oberflächengebundenen) metallorganischen Gerüstverbindungen ((SUR)MOFs). Zunächst wurden SURMOFs als potentielle Template für licht-induzierte freie radikalische Polymerisation hergestellt und untersucht. Grundlegende Studien für die Beladung solcher Gerüststrukturen mit Polybromstyrol wurden durchgeführt und mittels Röntgendiffraktometrie (XRD) und Flugzeit-Sekundärionen- Massenspektrometrie (ToF-SIMS) untersucht. Dabei wurden die SURMOFs am effizientesten über die Gasphase beladen und Modelpolymerisationen durchgeführt. Außerdem wurden die analytischen Möglichkeiten mittels Massenspektrometrie untersucht. Des Weiteren wurde festgestellt, dass hochauflösende Elektrosprayionisationsmassenspektrometrie angemessen für die Charakterisierung von Polymerisationen in SURMOFs ist. Anschließend wurde ein bifunktionaler Photoinitiator entwickelt und über Azid-Alkin-Cycloaddition in einer SURMOF-Gerüststruktur verankert, was mittels Infrarot-Reflektions-Absorptions-Spektroskopie (IRRAS) und ToF-SIMS bestätigt wurde. Der funktionalisierte SURMOF wurde in einer Quartzmikrowaage (QCM) unter Polymerisationbedingungen beobachtet und es wurde gezeigt, dass die Polymerisation von Methylmethacrylat initiiert werden konnte. Das Herauslösen des Polymers aus der Struktur und die anschließende Analyse durch Massenspektrometrie ist Gegenstand zukünftiger Untersuchungen. Der Photoinitiator, der für die Funktionalisierung von SURMOFs entwickelt wurde, wurde zudem für die Herstellung von Blockcopolymeren mittels λ-orthogonaler Chemie verwendet. Zunächst wurde Polyethylenglykol (PEG), ausgestattet mit einer Azid-Endgruppe, in einer kupferkatalysierten Azid-Alkin-Cycloaddition (CuAAC) bei sichtbarem Licht (λ = 420 nm) an die terminale Dreifachbindung des Photoinitiators gebunden. Der erhaltene PEG-Makroinitiator wurde mittels Massenspektrometrie charakterisiert und in Laserpuls-Polymerisationen (PLP) mit Methylmethacrylat umgesetzt (λ = 351 nm). Das erhaltene Blockcopolymer PEG-b-PMMA wurde mittels hochauflösender Größenausschlusschromatographie-Elektrosprayionisations-Massenspektrometrie (SEC-ESI-MS) analysiert. Für den Nachweis der λ-Orthogonalität des Systems wurde die Reihenfolge der Herstellungsschritte umgekehrt. Das heißt, die PLP wurde vor der Funktionalisierung mittels CuAAC durchgeführt. Beide Reaktionswege resultierten in vergleichbaren Massenspektren in der SEC-ESI-MS und die spezifischen Isotopenmuster konnten den entsprechenden Strukturen zugeordnet werden. Für licht-induzierte Stufenwachstumspolymerisationen in MOFs war die Synthese von Photomonomeren erforderlich, die eine AB Polycycloaddition eingehen. Zwei Monomere wurden entwickelt, die sowohl eine α-Methylbenzaldehyd-Einheit, als auch einen Fumarsäureester als Endgruppe tragen. Bei der Bestrahlung mit UV-Licht (λmax = 350 nm) in Dichlormethan polymerisieren beide Monomere, jedoch mit erheblichen Unterschieden in der Polymerisationsgeschwindigkeit und -Effizienz. Das Monomer mit dem aliphatischen Rückgrat wies eine höhere Zyklisierungstendenz als das Monomer mit dem aromatischen Rückgrat auf. Außerdem ergab die SEC-ESI-MS Analyse, dass das aliphatische Monomer anfällig für Endgruppenfragmentierung ist. Durch die Herstellung von Copolymeren beider Monomere wurde die Labilität der Endgruppen des aliphatischen Monomers bestätigt. Theoretische Berechnungen der Bindungsenergien der Monomere in ausgewählten MOF-Strukturen lassen vermuten, dass beide Monomere in die Strukturen diffundieren und damit vielversprechend für erfolgreiche MOF-Polymerisationen sind

Betriebsratsarbeit in logistischen Produktionsketten: Beispiel Automobilindustrie

"Mit der Herausbildung flexibler, kundenorientierter Organisationen in der Automobilindustrie ändert sich die Politik der Betriebsräte. Neue Produktionskonzepte setzen auf kleine, logistisch eng verknüpfte Einheiten. Die Betriebsräte reagieren auf Zergliederung und Auslagerung zunächst defensiv. Die Störanfälligkeit logistischer Ketten zwingt das Management ständig zu mitbestimmungspflichtigen Entscheidungen. Es ist auf die Kooperationsbereitschaft der Betriebsräte angewiesen. Deren Position wird stärker. Ihr Handeln trägt immer deutlicher Züge von Co-Management. Sie suchen die Kooperation mit dem Management, meiden jedoch keinesfalls die Konfrontation. Aber die Fraktalisierung fördert auch unterschiedliche Interessen zwischen den Betriebsräten. Vielerorts fehlt es noch an Methoden damit umzugehen. Hinter der Lösung dieses Problems steht der Aufbau von Kooperationen mit Betriebsräten der Zulieferer zurück." (Autorenreferat)"The role and policies of works councils are changing with the introduction of flexible, customer-oriented structures in the automobile industry. New concepts of production are generally based upon small, logistically connected units. At first, works councils have been reacting defensively to the processes of segmentation and outsourcing. Logistic chains are easily disrupted. In a system of co-determination, many of the necessary decisions can only be taken with the consent of the works council. Management therefore often depends on the works council's willingness to co-operate, thus strengthening the latter's position. Increasingly, works councils are being involved in co-management. Even so, they are by no means avoiding confrontation. Still, individualisation ('fractalisation') is causing differences of interest between the works councils of different firms. In many places, methods to deal with this problem have yet to be found. This often slows the development of cooperation with works councils in supplier companies." (author's abstract

The Diels-Alder Approach towards Cannabinoid Derivatives and Formal Synthesis of Tetrahydrocannabinol (THC)

Based on the Diels-Alder reaction of vinylchromenes with electron-poor dienophiles, we developed a strategy for the synthesis of tetrahydrocannabinol derivatives. Substituted vinyl chromenes could be converted with several dienophiles to successfully isolate several complex molecules. These molecules already contain the cannabinoid-like base structure and further processing of one such derivative led to a precursor of Delta(9)-tetrahydrocannabinol. The most challenging step towards this precursor was an epoxidation step that was ultimately achieved via dimethyl dioxirane.Peer reviewe

Targeting oxidative stress: Novel coumarin-based inverse agonists of GPR55

Oxidative stress is associated with different neurological and psychiatric diseases. Therefore, development of new pharmaceuticals targeting oxidative dysregulation might be a promising approach to treat these diseases. The G-protein coupled receptor 55 (GPR55) is broadly expressed in central nervous tissues and cells and is involved in the regulation of inflammatory and oxidative cell homeostasis. We have recently shown that coumarin-based compounds enfold inverse agonistic activities at GPR55 resulting in the inhibition of prostaglandin E2. However, the antioxidative effects mediated by GPR55 were not evaluated yet. Therefore, we investigated the antioxidative effects of two novel synthesized coumarin-based compounds, KIT C and KIT H, in primary mouse microglial and human neuronal SK-N-SK cells. KIT C and KIT H show antioxidative properties in SK-N-SH cells as well as in primary microglia. In GPR55-knockout SK-N-SH cells, the antioxidative effects are abolished, suggesting a GPR55-dependent antioxidative mechanism. Since inverse agonistic GPR55 activation in the brain seems to be associated with decreased oxidative stress, KIT C and KIT H possibly act as inverse agonists of GPR55 eliciting promising therapeutic options for oxidative stress related diseases

Civil Society Monitoring Report on the Implementation of the National Roma Integration Strategy and Decade Action Plan in 2012 in: the Czech Republic

The situation of the Roma minority is one of the Czech Republic's most urgent social and human rights problems. The Czech Republic seeks to address this complex problem with a wide range of activities. The overall direction of the Czech Republic's integration policy is defined in two strategic documents: the Concept for Roma Integration 2010-2013 and the Strategy for Combating Social Exclusion 2011-2015. The former document has at the same time the status of the Czech Republic's National Strategy for Roma Inclusion (NSRI), as it was translated and sent to Brussels in response to the European Commission's request to all member states to develop national strategies for Roma inclusion. Initiated by the Decade of Roma Inclusion Secretariat Foundation and written by a coalition of Czech non-governmental organisations (NGOs), this report is intended to provide an independent assessment of the Czech Republic's progress in achieving the goal of Roma inclusion as defined in the Concept for Roma Integration/Czech NSRI. Focussing on six topics: education, employment, health, housing, anti discrimination, and structural requirements, the European Commission provided the member states with feedback on their strategies and made recommendations as to how the strategies could be improved. With a view to providing additional feedback from the perspective of civic society organisations, the Decade Secretariat decided that the independent civic society reports would focus on the same topics.Due to this decision, this report does not cover all the dimensions of Roma integration that are covered by the Czech Concept for Roma Integration, which also includes chapters on the support of Roma identity and culture. However, the decision to limit this report to the social, economic and legal aspects of Roma integration should in no way be interpreted as a disregard for questions related to Roma identity and empowerment. On the contrary, the authors demonstrate throughout the report how the hitherto applied integration strategies fail to give the Roma communities a chance to participate actively in the process of integration. One of the most important challenges for the coming years will be to develop funding mechanisms that will be more accessible for Roma and to introduce better mechanisms for the participation of Roma in decision-making. The first part of this summary follows the report's thematic structure. In the case of each of the six thematic chapters a few key messages will be highlighted. The full text of this report provides more comprehensive information on particular policies and programmes. The second part of this summary has been used to draw attention to three particular cross-sectoral challenges which have surfaced in many of the thematic chapters

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE$_{2}$-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE$_{2}$-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis

Effects of a Novel GPR55 Antagonist on the Arachidonic Acid Cascade in LPS-Activated Primary Microglial Cells

Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G-protein-coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 µM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)-treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin $E_{2}$ ($PGE_{2}$), reduced microsomal $PGE_{2}$ synthase (mPGES-1) and cyclooxygenase-2 (COX-2) synthesis, and inhibited the phosphorylation of Ikappa B-alpha (IκB-α), a crucial upstream step of the inflammation-related nuclear factor-kappaB (NF-κB) signaling pathway. However, no effects were observed on COX-1 and -2 activities and mitogen-activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX-2/$PGE_{2}$ pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression

Synthesis and SAR evaluation of coumarin derivatives as potent cannabinoid receptor agonists

We report the development and extensive structure-activity relationship evaluation of a series of modified coumarins as cannabinoid receptor ligands. In radioligand, and [S-35]GTP gamma S binding assays the CB receptor binding affinities and efficacies of the new ligands were determined. Furthermore, we used a ligand-based docking approach to validate the empirical observed results. In conclusion, several crucial structural requirements were identified. The most potent coumarins like 3-butyl-7-(1-butylcyclopentyl)-5-hydroxy-2H-chromen-2-one (36b, K-i CB2 13.7 nM, EC50 18 nM), 7-(1-butylcyclohexyl)-5-hydroxy-3-propyl-2H-chromen-2-one (39b, K-i CB2 6.5 nM, EC50 4.51 nM) showed a CB2 selective agonistic profile with low nanomolar affinities. (C) 2021 Published by Elsevier Masson SAS.Peer reviewe