E-Dissertationen

Photoswitchable Ligands Enable Thermodynamic Disequilibration of Metal-Organic Assemblies

Tue, 14 Apr 2026 00:00:00 GMT

Photoswitchable Ligands Enable Thermodynamic Disequilibration of Metal-Organic Assemblies Notheis, Maximilian Johannes Living organisms need a constant supply of energy to sustain life. The molecular reason for this can be found in the operating mechanism of biological systems that perform extraordinary functions like absorbing nutrients and distributing them across the organism, self-healing, movement, and reproduction. These intricate biological systems do not reside in the thermodynamic minimum. Instead, a constant energy supply is needed to sustain meta-stable states far away from the thermodynamic minimum. The innate energy of these states is harnessed to perform work, enabling the complex behaviors of living organisms.
A fundamental understanding of how to access and sustain meta-stable states in artificial systems and materials is a step towards extending life-like behaviors to inanimate objects, opening numerous perspectives from more sustainable self-repairing materials to medical applications in targeted drug release. Systems making use of phase boundaries to stabilize meta-stable states such as dynamic droplets and nanocrystals have recently been described in literature. However, the systematic use of dynamic and reversible metal-ligand interactions to stabilize meta-stable states remains an underexplored approach.
This dissertation establishes light-driven reaction networks, specifically energy ratchets, as a foundational mechanism to accumulate meta-stable states in self-assembled metal-organic structures. Furthermore, it explores how the innate energy of the meta-stable state can be harnessed in enabling macroscale spatio-temporal control over nanoscale chemical transformations.
Initial work focused on the design, synthesis and investigation of photoresponsive building blocks. Firstly, a family of novel twelve-membered macrocyclic azobenzenes was investigated, yielding new insights on using backbone flexibility to tune photochromic properties. Secondly, a reliable gram‑scale synthesis of 2,8-dihalogenated diazocine was established. This was followed by selective, stepwise Suzuki couplings to access asymmetrically functionalized diazocine building blocks that combine a large geometry change during switching with favorable photochemical properties.
A one-pot sub-component self-assembly using one of the tailor-made building blocks resulted in selective formation of high-fidelity, low-symmetry, heterobimetallic helicates. The final structure contains two distinct coordination sites, enabling quantitative formation of self-sorted Fe/Zn and Zn/Co heterobimetallic helicates. The precise metal distribution is enabled by a complex reaction network during self-assembly that amplifies differences in metal-ligand bond strength and exchange kinetics. This separates the metals into the two coordination sites as a result of kinetic and thermodynamic factors.
Investigating the photoresponsive behavior of the helicates revealed a light-driven energy-ratchet mechanism. Photoisomerization of the diazocine units transiently reshapes the assemblies' energy landscape, enabling rapid reconfiguration of the initial structure into a mixture of metastable isomeric states. These become kinetically trapped upon back-isomerization, enabling the accumulation of meta-stable high-energy atropisomers. Continuous white-light irradiation operates the energy ratchet autonomously by exciting both switching transitions simultaneously. This amplifies a minor photostationary state into a dominant, long-lived meta-stable diastereomer. Additionally, operation of the ratchet accelerates regioselective metal-cation exchange (Zn₂L → ZnFeL), providing spatiotemporal control over selective metal ion capture.
Nature shows us that complex behavior is a result of complex systems. The incorporation of energy ratchets into metal-organic cages elevates them into a realm of complexity that is usually reserved for enzymes. These results pave the way towards larger photoresponsive cages for molecular machines that operate under out‑of‑equilibrium conditions, thus enabling life-like behaviors such as controlled catalysis, active transport, or macroscale directed movement.

Role of SUMOylation in mitochondrial protein import and quality control

Tue, 14 Apr 2026 00:00:00 GMT

Role of SUMOylation in mitochondrial protein import and quality control Mishra, Swadha (noch nicht zugänglich / not yet accessible)

Synthesis of P2Y₁₂ receptor antagonists as therapeutics and diagnostics

Mon, 13 Apr 2026 00:00:00 GMT

Synthesis of P2Y₁₂ receptor antagonists as therapeutics and diagnostics Al Musawi, Hashem Ali M. The P2Y₁₂ receptor (P2Y₁₂R), a G protein-coupled receptor activated by adenosine diphosphate (ADP), has traditionally been associated with platelet aggregation and targeted for antithrombotic therapy. More recently, its expression on microglial cells in the central nervous system (CNS) has attracted considerable interest, as it plays a central role in neuroinflammatory processes and represents a promising biomarker for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy. Targeting microglial P2Y₁₂Rs enables modulation of its function and offers an avenue for imaging neuroinflammatory processes. In this context, the present dissertation focuses on the design, synthesis, characterization, and evaluation of novel P2Y₁₂R antagonists, with particular emphasis on radiolabeled ligands, and blood-brain barrier (BBB)-permeable compounds for both therapeutic and diagnostic applications.
The first part of this work explores structural modifications of anthraquinone derivatives guided by molecular docking studies performed on sodium 1-amino-9,10-dioxo-4-((4-(phenylamino)-3-sulfonatophenyl)amino)-9,10-dihydroanthracene-2-sulfonate (PSB-0739), a potent and selective P2Y₁₂R antagonist. These studies highlighted synthetic strategies to enable substitution at the C6- and C7-positions of the anthraquinone core and to modify the aniline moiety, followed by the synthesis of the targeted final compounds via Ullmann coupling. This systematic structure-activity relationship (SAR) study provided new insights into the chemical space surrounding the anthraquinone scaffold within the binding pocket and led to the synthesis of novel P2Y₁₂R antagonist radioligand precursors as a basis for the development of radioligands.
In the second part, efforts were directed towards the development of radiolabeled anthraquinone-based P2Y₁₂R antagonists. Radioligands hold promise as diagnostic tools for non-invasive imaging of microglial activation, thereby supporting early detection and monitoring of neurodegenerative disorders. However, the chemical instability of the 2-sulfo- and 2-carboxyanthraquinone derivatives, particularly the release of the C2-sulfonate or carboxylic acid groups under palladium-catalyzed hydrogenation conditions, has limited their use as indicated by three synthetic trials starting with three different precursors. To address this challenge, a model compound was developed and investigated to optimize key reaction parameters, including catalyst type, solvent system, and hydrogen pressure. These studies identified suitable conditions, thus laying the foundation for the preparation of radioligands suitable for imaging applications.
The third part of this dissertation shifts focus from anthraquinones to a systematic evaluation of published P2Y₁₂R antagonists with regard to their suitability as CNS-permeable lead structures. Since microglial P2Y₁₂Rs provide an attractive marker for imaging neuroinflammation through positron emission tomography (PET), identifying scaffolds with favorable BBB-penetration is of high relevance. A comprehensive review of available antagonists was performed, combining physicochemical property analysis with in silico CNS penetration filters and SAR assessment. This approach identified a pyrazolyl-phenyl-carbamoyl-indole scaffold as particularly promising. Within this series, substitution patterns were defined that improve potency and hold potential of CNS bioavailability. These findings provide a roadmap for the rational design of novel P2Y₁₂R antagonists optimized for CNS applications.
Building on these evaluations, the fourth part of the work describes the development and pharmacological characterization of [³H]PSB-22219, a novel non-nucleotidic P2Y₁₂R antagonist radioligand. The unlabeled compound demonstrated high metabolic stability in rat liver microsomes and selectivity over other ADP-activated receptors. [³H]PSB-22219 exhibited high-affinity binding to human P2Y₁₂Rs expressed in recombinant cell systems (K_D = 4.57 nM) with very low nonspecific binding. Importantly, radioligand binding assays confirmed nanomolar affinity to native receptors in human platelets (K_D = 2.53 nM), rat brain cortex (K_D = 5.35 nM), and mouse microglia (K_D = 269 nM), with microglia displaying exceptionally high receptor density. Autoradiography studies further demonstrated visualization of human P2Y₁₂R expression in the brain of a humanized rat model. Together, these results establish [³H]PSB-22219 as a valuable pharmacological tool for probing P2Y₁₂R biology and as a promising candidate for radiodiagnostic development.
Finally, the lead structure [³H]PSB-22219 was taken as a starting point for the design, synthesis, and establishment of structure-property relationship (SPR) studies to identify novel, potent, selective, and metabolically stable P2Y₁₂R antagonists with favorable permeability properties. The identified candidates present opportunities for direct application as P2Y₁₂-targeted therapeutics as well as for chemical radiolabeling to enable CNS imaging.

Role of the tetraspanin CD151 in the early human papillomavirus type 16 infection cascade

Fri, 10 Apr 2026 00:00:00 GMT

Role of the tetraspanin CD151 in the early human papillomavirus type 16 infection cascade Massenberg, Annika Human papillomaviruses (HPV) are a diverse group of non-enveloped, double-stranded DNA viruses with profound significance in human health. An estimated 5% of all human cancer cases are attributed to HPVs. For infection to occur, virions must reach dividing basal cells of the lower epithelium through a break in the epithelial barrier. On the basement membrane, viral particles bind to their primary attachment site, heparan sulfate (HS) within the extracellular matrix (ECM). This binding triggers a series of conformational changes which promote viral cell entry, with virions migrating along actin-rich protrusions to engage a yet uncharacterized secondary receptor complex on keratinocytes. Current evidence suggests that this secondary receptor is likely a multimeric complex rather than a single molecular entity. Several proteins have been implicated as essential for cell entry, including the tetraspanin CD151, integrin-α6 and growth factor receptors. Among these, CD151 plays a crucial role in facilitating viral access and organizing the cellular components necessary for successful infection. However, this multistep entry process is slow and asynchronous, and involvement of CD151 in HPV entry prior to endocytosis remains unclear.
In this study, HPV16 pseudovirions (PsVs) were used to investigate early infection stages and their association with CD151. PsV/CD151 assemblies were analyzed, revealing that PsVs preferentially bind to regions with increased CD151 density. Overexpression of CD151-GFP induced the formation of large CD151 aggregates, although these aggregates also form independently of PsV binding, indicating that aggregate formation depends on CD151 expression levels.
Furthermore, the actin inhibitor cytochalasin D was employed to synchronize PsV uptake, revealing that actin dynamics within filopodia are crucial for releasing virions from the ECM and transferring them to the cell body. The human keratinocyte cell line HaCaT was validated as an ideal model system for studying early HPV infection events. Inhibition of actin-dependent processes resulted in entrapment of PsVs in the ECM. Upon removal of this blockade, HS-coated PsVs rapidly translocated to the cell body and to CD151 assemblies. After reaching the cell body, the viral capsid sheds its HS coat, followed by PsV/CD151 endocytosis. These findings demonstrate an early involvement of CD151 in HPV16 cell entry.
Moreover, the HSPG-binding peptide 19-2.5 was evaluated for its potential to inhibit PsV infection. While peptide 19-2.5 did not affect PsV/CD151 association, it caused the formation of large viral aggregates several micrometers away from the plasma membrane, indicating a block in the translocation from the primary HSPG attachment site to the secondary receptor complex. This suggests that peptide 19-2.5 may serve as a promising alternative or complement to current HPV prevention strategies.

E-Dissertationen

Photoswitchable Ligands Enable Thermodynamic Disequilibration of Metal-Organic Assemblies

Role of SUMOylation in mitochondrial protein import and quality control

Synthesis of P2Y12 receptor antagonists as therapeutics and diagnostics

Role of the tetraspanin CD151 in the early human papillomavirus type 16 infection cascade

Synthesis of P2Y₁₂ receptor antagonists as therapeutics and diagnostics