540 Chemie und zugeordnete Wissenschaften
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N\(^6\)-methyladenosine (m\(^6\)A) is an important modified nucleoside in cellular RNA associated with multiple cellular processes and is implicated in diseases. The enzymes associated with the dynamic installation and removal of m\(^6\)A are heavily investigated targets for drug research, which requires detailed knowledge of the recognition modes of m\(^6\)A by proteins. Here, we use atomic mutagenesis of m\(^6\)A to systematically investigate the mechanisms of the two human m\(^6\)A demethylase enzymes FTO and ALKBH5 and the binding modes of YTH reader proteins YTHDF2/DC1/DC2. Atomic mutagenesis refers to atom-specific changes that are introduced by chemical synthesis, such as the replacement of nitrogen by carbon atoms. Synthetic RNA oligonucleotides containing site-specifically incorporated 1-deaza-, 3-deaza-, and 7-deaza-m\(^6\)A nucleosides were prepared by solid-phase synthesis and their RNA binding and demethylation by recombinant proteins were evaluated. We found distinct differences in substrate recognition and transformation and revealed structural preferences for the enzymatic activity. The deaza m\(^6\)A analogues introduced in this work will be useful probes for other proteins in m\(^6\)A research.
In this thesis, a new approach of a qNMR method has been investigated to demonstrate the reliability and importance of this method as an alternative solution for analyzing oil quality parameters, especially in RFO, which has particular characteristics (red color). This study also includes the chemometric evaluation of spectral data for authentication, visual grouping, and prediction of RFO quality based on the degree of unsaturation, FFA value, and unsaturated fatty acid content.
The analytical measurement procedure of NMR spectroscopy begins with optimization of the analytical acquisition parameters, including effect of solvent, effect of sample concentration, selection of appropriate internal standards, determination of T1, and method validation. Furthermore, the results of the method development were interpreted to RFO samples evaluation, which began with determining the assignment of signal spectra for the determination of AV, SV, EV, and IV simultaneously with: the hydrolysis approach and standard addition of palmitic acid.
In DNA-encoded library synthesis, amine-substituted building blocks are prevalent. We explored isocyanide multicomponent reactions to diversify DNA-tagged amines and reported the Ugi-azide reaction with high yields and a good substrate scope. In addition, the Ugi-aza-Wittig reaction and the Ugi-4-center-3-component reaction, which used bifunctional carboxylic acids to provide lactams, were explored. Five-, six-, and seven-membered lactams were synthesized from solid support-coupled DNA-tagged amines and bifunctional building blocks, providing access to structurally diverse scaffolds.
The binding of drugs to plasma proteins is an important process in the human body and has a significant influence on pharmacokinetic parameter. Human serum albumin (HSA) has the most important function as a transporter protein. The binding of ketamine to HSA has already been described in literature, but only of the racemate. The enantiomerically pure S-ketamine is used as injection solution for induction of anesthesia and has been approved by the Food and Drug Administration for the therapy of severe depression as a nasal spray in 2019. The question arises if there is enantioselective binding to HSA. Hence, the aim of this study was to investigate whether there is enantioselective binding of S-and R-ketamine to HSA or not. Ultrafiltration (UF) followed by chiral capillary electrophoretic analysis was used to determine the extent of protein binding. Bound fraction to HSA was 71.2 % and 64.9 % for enantiomerically pure R- and S-ketamine, respectively, and 66.5 % for the racemate. Detailed binding properties were studied by Saturation Transfer Difference (STD)-, waterLOGSY- and Carr-Purcell-Meiboom-Gill (CPMG)-NMR spectroscopy. With all three methods, the aromatic ring and the N-methyl group could be identified as the structural moieties most strongly involved in binding of ketamine to HSA. pK\(_{aff}\) values determined using UF and NMR indicate that ketamine is a weak affinity ligand to HSA and no significant differences in binding behavior were found between the individual enantiomers and the racemate.
Drug Discovery based on Oxidative Stress and HDAC6 for Treatment of Neurodegenerative Diseases
(2024)
Most antioxidants reported so far only achieved limited success in AD clinical trials. Growing evidences suggest that merely targeting oxidative stress will not be sufficient to fight AD. While multi-target directed ligands could synergistically modulate different steps in the neurodegenerative process, offering a promising potential for treatment of this complex disease.
Fifteen target compounds have been designed by merging melatonin and ferulic acid into the cap group of a tertiary amide HDAC6 inhibitor. Compound 10b was screened as the best hybrid molecule exhibit potent HDAC6 inhibition and potent antioxidant capacity. Compound 10b also alleviated LPS-induced microglia inflammation and led to a switch from neurotoxic M1 to the neuroprotective M2 microglial phenotype. Moreover, compound 10b show pronounced attenuation of spatial working memory and long-term memory damage in an in vivo AD mouse model. Compound 10b can be a potentially effective drug candidate for treatment of AD and its druggability worth to be further studied.
We have designed ten novel neuroprotectants by hybridizing with several common antioxidants, including ferulic acid, melatonin, lipoic acid, and trolox. The trolox hybrid compound exhibited the most potent neuroprotective effects in multiple neuroprotection assays. Besides, we identified the synergistic effects between trolox and vitamin K derivative, and our trolox hybrid compound showed comparable neuroprotection with the mixture of trolox and vitamin K derivative.
We have designed and synthesized 24 quinone derivatives based on five kinds of different quinones including ubiquinone, 2,3,5-trimethyl-1,4-benzoquinone, memoquin, thymoquinone, and anthraquinone. Trimethylbenzoquinone and thymoquinone derivatives showed more potent neuroprotection than other quinones in oxytosis assay. Therefore, trimethylbenzoquinone and thymoquinone derivatives can be used as lead compounds for further mechanism study and drug discovery for treatment of neurodegenerative disease.
We designed a series of photoswitchable HDAC inhibitors, which could be effective molecular tools due to the high spatial and temporal resolution. In total 23 target compounds were synthesized and photophysicochemically characterized. Azoquinoline-based compounds possess more thermally stable cis-isomers in buffer solution, which were further tested in enzyme-based HDAC inhibition assay. However, none of those tested compounds show significant differences in activities between trans-isomers and corresponding cis-isomers.
The demand for LIB with enhanced energy densities leads to increased utilization of the space within the confinements of the battery housing or to the use of electrode material with increased intrinsic specific energy densities. Both requirements result in more stress on the battery electrodes and separator during cycling or aging. However, the effect of mechanical strain on the cell’s electrochemistry and thus the performance of batteries is rather unexplored compared to the impact of current or temperature, for example. The objective of this thesis was to give a better understanding of the electrochemical and mechanical interplay in current- and next-generation lithium based battery cells. Therefore, the thesis was structured into the investigations on SoA and next-generation LIBs. For SoA LIBs, the investigations of the interplay started at laboratory scale. Here, the expansion of various electrodes and also the impact of mechanical pressure and its distribution on the performance of the cells were
studied. The investigations at laboratory scale was followed by an examination of the electrochemical and mechanical interactions on large format commercial LIBs which are used in BEVs. Accordingly, the effect of bracing and its effect on the performance was studied in an aging and post-mortem study. To gain a deeper understanding of the mechanical changes in LIBs, an ultrasonic study was performed for pouch cells. Here, the mechanical changes were further investigated in dependence of SoC and SoH. The effects of the mechanical stress on the performance for next-generation batteries were studied at laboratory scale. In the beginning, the expansion of next-generation anode materials such as silicon and lithium was compared with today’s anode materials. Furthermore, the effect of mechanical pressure and electrolyte on the irreversible dilation and performance was investigated for lithium metal cells. Overall, it was shown that pressure has a significant effect on the performance of today’s and also future LIBs. The interplay of the electrochemical and mechanical effects inside a LIB has a considerable impact on the lifetime, capacity fading and impedance increase of the batteries.
In this thesis, we apply the information-theoretic approach in the context of quantum dynamics and wave packet motion: Information-theoretic measures are calculated from position and momentum densities, which are obtained from time-dependent quantum wave functions. The aim of this thesis is to benchmark, analyze and interpret these quantities and relate their features to the wave packet dynamics. Firstly, this is done for the harmonic oscillator (HO) with and without static disorder. In the unperturbed HO, the analytical study of coherent and squeezed states reveals time-dependent entropy expressions related to the localization of the wave function. In the disordered HO, entropies from classical and quantum dynamics are compared for short and long times. In the quantum case, imprints of wave packet revivals are found in the entropy. Then, the energy dependence of the entropy for very long times is discussed. Secondly, this is donefor correlated electron-nuclear motion. Here, entropies derived from the total, electronic and nuclear density, respectively, are calculated in position and momentum space for weak and strong adiabatic electronic coupling. The correlation between electron and nucleus is investigated using different correlation measures, where some of these functions are sensitive to the nodal structure of the wave function. An analytic ansatz to interpret the information-theoretical quantities is applied as well.
This work aims at elucidating chemical processes involving homogeneous catalysis and photo–physical relaxation of excited molecules in the solid state. Furthermore, compounds with supposedly small singlet–triplet gaps and therefore biradicaloid character are investigated with respect to their electro–chemical behavior. The work on hydroboration catalysis via a reduced 9,10–diboraanthracene (DBA) was preformed in collaboration with the Wagner group in Frankfurt, more specifically Dr. Sven Prey, who performed all laboratory experiments. The investigation of delayed luminescence properties in arylboronic esters in their solid state was conducted in collaboration with the Marder group in Würzburg. The author of this work took part in the synthesis of the investigated compounds while being supervised by Dr. Zhu Wu. The final project was a collaboration with the group of Anukul Jana from Hyderabad, India who provided the experimental data.
Poor or variable oral bioavailability is of major concern regarding safety and efficacy for the treatment of patients with poorly water-soluble drugs (PWSDs). The problem statement of this work involves a pharmaceutical development perspective, the physicochemical basis of the absorption process and physiological / biopharmaceutical aspects. A methodology was developed aiming at closing the gap between drug liberation and dissolution on the one hand and the appearance of drug in the blood on the other. Considering what is out of control from a formulation development perspective, a clear differentiation between bioavailability and bioaccessibility was necessary. Focusing on the absorption process, bioaccessibility of a model compound, a poorly soluble but well permeable weak base, was characterized by means of flux across artificial biomimetic membranes. Such setups can be considered to reasonably mimic relevant oral absorption resistances in vitro in terms of diffusion through an unstirred water layer (UWL) and a lipidic barrier. Mechanistic understanding of the driving force for permeation was gained by differentiating drug species and subsequently linking them to the observed transfer rates using a bioaccessibility concept. The three key species that need to be differentiated are molecularly dissolved drug, drug associated in solution with other components (liquid reservoir) and undissolved drug (solid reservoir). An innovative approach to differentiate molecularly dissolved drug from the liquid reservoir using ultracentrifugation in combination with dynamic light scattering as control is presented. A guidance for rational formulation development of PWSDs is elaborated based on the employed model compound. It is structured into five guiding questions to help drug formulation scientists in selecting drug form, excipients and eventually the formulation principle. Overall, the relevance but also limitations of characterizing bioaccessibility were outlined with respect to practical application e.g. in early drug formulation development.
Based on previous results showing that thioether modification of gold nanoparticles (AuNPs), especially coating with a multivalent system, yielded in excellent colloidal stability, the first aim of this thesis was to prove whether functionalization of silver nanoparticles (AgNPs) with thioether also has a comparable or even enhanced stabilization efficacy compared with the gold standard of coating with thiols and, particularly, whether the multivalency of polymers leads to stable AgNPs conjugates. Herein, AgNPs coated with mono- and multivalent thiol- and thioether polymers were prepared to systematically investigate the adsorption kinetics onto the silver surface as well as the colloidal stability after exposure to different conditions relevant for biomedical application. Although the thioether-polymers showed a slower immobilization onto AgNPs, same or mostly even better stabilization was exhibited than for the thiol analogs.
As multivalent thioether-poly(glycidol) (PG) is already proven as a promising candidate for AuNP modification and stabilization, the second aim of this thesis was to examine the stealth behavior of thioether-PG, side-chain functionalized with various hydrophobic (alkyl and cholesteryl) units, to gain a deeper understanding of AuNP surface functionalization in terms of protein adsorption and their subsequent cellular uptake by human monocyte-derived macrophages. For this purpose, citrate-stabilized AuNPs were modified with the amphiphilic polymers by ligand exchange reaction, followed by incubation in human serum. The various surface amphiphilicities affected protein adsorption to a certain extent, with less hydrophobic particle layers leading to a more inhibited protein binding. Especially AuNPs functionalized with PG carrying the longest alkyl chain showed differences in the protein corona composition compared to the other polymer-coated NPs. In addition, PGylation, and especially prior serum incubation, of the NPs exhibited reduced macrophage internalization.
As the use of mammals for in vivo experiments faces various challenges including increasing regulatory hurdles and costs, the third aim of this thesis was to validate larvae of the domestic silkworm Bombyx mori as an alternative invertebrate model for preliminary in vivo research, using AuNPs with various surface chemistry (one PEG-based modification and three PG-coatings with slightly hydrophobic functionalization, as well as positively and negatively charges) for studying their biodistribution and elimination. 6 h and 24 h after intra-hemolymph injection the Au content in different organ compartments was measured with ICP-MS, showing that positively charged particles appeared to be eliminated most rapidly through the midgut, while AuNPs modified with PEG, alkyl-functionalized PG and negatively charged PG exhibited long-term bioavailability in the silkworm body.