Tailor made organic molecules for electronic applications

Within this thesis, the synthesis of functional molecules with specific characteristics and a wide application spectrum was of major interest. Due to the nature of their applications, it is rather difficult to categorize all the designed molecules within one general topic. For the purpose of a clearly represented structure, this work is divided in three individual chapters, each treating one independent topic by its own introduction, synthetic strategy, results and conclusion. Chapter 1 - Surface Functionalization Protection groups for alkynes, representing structural building blocks in various chemical applications, are sensitive to a fluoride source or basic conditions. The synthetic accessibility and efficient functionalization by click chemistry of the alkyne moiety makes them interesting target structures in surface functionalization approaches. A main challenge is the site-selective functionalization of a surface. To address this challenge, an electrochemically cleavable protecting group for alkynes was developed. The immobilization of the designed molecules on TiO2 surfaces was achieved with an EDTA based anchoring group, linked by a phenyl ethylene moiety to the protected alkyne. Upon reduction of the naphthoquinone based protecting group, an intramolecular ring formation forces the release of the alkyne moiety, which remains immobilized on the TiO2 surface. The site-selectivity was achieved by dividing a wafer into electronically separated sections. By applying a potential of -0.9 V vs. SCE on individual areas of the wafer, selective deprotection was achieved. The received free alkyne moieties were further functionalized with naphthalene diimide based azide dyes by copper catalyzed 1,3-dipolar Huisgen cycloaddition reactions. To confirm the individual steps of the procedure, solid-state UVVis measurements were performed. Chapter 2 - Molecular Wires The scientific challenge to build electronic circuits by bottom-up approaches in a nanometer scale appealed generation of chemists. With organic synthetic techniques, an atomic precision in the structural design is achievable and enables the creation of identical molecules in large quantities. The understanding of structural and electronical characteristics and their influences on the behavior of molecules in electronic circuits has risen during the last decade. As consequence, molecules acting as molecular wires, rectifiers, switches or memory elements have been developed. Most of the conformation effects contributing to the conductivity of molecular wires were investigated with rather short molecules. By elongate the molecular wires, a change in the transport mechanism was reported in literature from a tunneling to a hopping process. Therefore, new molecules were designed with a length within the determined mechanism changing range. The molecular design was based on already investigated biphenyl structures with defined inter-plane angles, to determine if the same conformation effects were observable in the elongated analogues. The second part of this chapter is based on an earlier study with a bipyridyl derivative[1], which has shown a switch between an “on” state of higher conductance and “off” state with lower conductance in break junction measurements. The switching was achieved by applying a positive or negative voltage in the range of ± 0.9 V. The state of the molecule was readable by the conductance difference of both states at an applied potential, lower than the required switching potential. To further investigate this phenomenon, biphenyl derivatives with electron withdrawing and electron donating moieties were synthesized. The resulting intrinsic dipole moment of the molecules is considered crucial for the switching behavior. Chapter 3 - High-Triplet State Energy Materials Used as building blocks for organic light emitting diodes (OLED), 4,4’-dicarbazole-1,1’-biphenyl (CBP) derivatives are of major interest in the field of electrophosphorescence.[2] Carbazole moieties in CBP provide a high triplet energy state and thereby enable the use as matrix materials with an efficient energy transfer to a phosphorescence light emitting dye.[3] For an efficient triplet energy transfer, especially for deep blue light emitting dyes, the triplet energy state of the matrix material should be higher than 2.7 eV. Five new CBP derivatives were synthesized by introducing sterically demanding substituents to the carbazole subunit in 1,8-position or to the biphenyl backbone. With these modifications, a perpendicular alignment between the carbazole subunit and the biphenyl backbone was achieved, resulting in a decreased π-conjugation through the molecule and therefore an increased triplet state energy. Furthermore, by introducing electron withdrawing and electron donating groups at the carbazole subunit, a shift of the HOMO / LUMO level was achieved.[4

Interplay between CFTR Phosphorylation, CFTR-ATPase Activity, and Anion Flux

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR, ABCC7), mutations of which cause CF, belongs to the ATP binding cassette (ABC) transporter family and works as a channel for small anions, such as chloride and bicarbonate. Anion channel activity is known to depend on phosphorylation by cAMP-dependent protein kinase A (PKA) and CFTR-ATPase activity. Whereas anion channel activity has been extensively investigated, phosphorylation and CFTR-ATPase activity are still poorly understood. Here, we show that the two processes can be measured in a label-free and non-invasive manner in real time in live cells, stably transfected with CFTR. This study reveals three key findings. (i) The major contribution to the total CFTR-related ATP hydrolysis rate (≥ 90 %) is due to phosphorylation by PKA and the minor contribution (≤ 10 %) to CFTR-ATPase activity. (ii) The mutant CFTR-E1371S which is still conductive, but defective in ATP hydrolysis, is not phosphorylated, suggesting that phosphorylation requires a functional nucleotide binding domain and occurs in the post-hydrolysis transition state. (iii) CFTR-ATPase activity is inversely related to CFTR anion flux. The present data are consistent with a model in which CFTR is in a closed conformation with two ATPs bound. The open conformation is induced by ATP hydrolysis and corresponds to the post hydrolysis transition state which is stabilized by phosphorylation and binding of chloride channel potentiators

New 4,4'-Bis(9-carbazolyl)-Biphenyl Derivatives with Locked Carbazole-Biphenyl Junctions: High-Triplet State Energy Materials

We synthesized a series of 4,4'-bis(9-carbazolyl)-biphenyl (CBP) derivatives, using methyl groups as spatially demanding groups, locking the angle between the carbazole subunit and the biphenyl backbone as potential matrix material for blue organic light-emitting diodes (OLEDs). The locked rotation was achieved by four methyl groups either in positions 1 and 8 of the carbazole subunit (1) or in positions 3, 5, 3', and 5' of the biphenyl subunit (2), and the fixed spatial arrangement was confirmed by X-ray analysis. The physical properties of CBP derivatives based on parent structure 2 were further tailored by electron-withdrawing CF3 groups in positions 3 and 6 (3) or positions 2 and 7 of the carbazole subunits (4) or alternatively by electron-donating CH3O groups in positions 2 and 7 (5) of the same building blocks. Increased triplet energies (ET) compared to that of the parent compound CBP were found for all synthesized CBP derivatives 1-5. Enhanced glass transition temperatures ranging between 129 and 202 °C further corroborate the application potential of these derivatives for matrix material in blue OLEDs

Electrochemical Multiplexing: Control over Surface Functionalization by Combining a Redox-Sensitive Alkyne Protection Group with "Click"-Chemistry

Local functionalization of surfaces is a current technological challenge. An electrochemically addressable alkyne protection group is presented enabling the site-selective liberation of alkynes exclusively on electrified electrodes. This controlled deprotection is based on a mendione chromophore which becomes a strong enough nucleophile upon reduction to intramolecularly attack the trialkylsilane alkyne protection group. The site-selective liberation of the alkyne is demonstrated by immobilizing the protected alkyne precursor on a transparent TiO2 electrode and subsequently immobilizing red and blue azide dyes by azide-alkyne "click"-chemistry. While the proof-of-principle is based on colorations visible to the bare eye, the technique presented is generic also to nontransparent electrodes, microscale separations, and functional moieties other than dyes. It may open manifold applications where site-selective functionalization is required but hardly realizable with conventional methods

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study

The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n = 14), with MCI unlikely due to AD (MCIother, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3+CD8−IL-17A+IFNγ− Th17 cells, CD3+CD8−IL-17A−IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8−IL-17A+IFNγ− Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (rTreg|totalTau = 0.43, p = 0.021, n = 28; rTreg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (rTreg|totalTau = −0.51, p = 0.007, n = 26). The increase of circulating CD3+CD8−IL-17A+IFNγ− Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD

image_2_Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study.tif

<p>The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (T_h) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCI_AD, n = 14), with MCI unlikely due to AD (MCI_other, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells, CD3⁺CD8⁻IL-17A⁻IFNγ⁺ Th1 cells, and CD4⁺CD127^lowCD25⁺ regulatory T cells (T_regs) were assessed by flow cytometry. In addition, the correlations of the proportions of T_h subsets to cerebrospinal fluid biomarkers were studied. CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells were significantly increased in subjects with MCI_AD compared to age- and sex-matched subjects with MCI_other and controls (MCI_AD mean = 1.13, SD = 0.77; MCI_other mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4⁺CD127^lowCD25⁺ T_regs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (r_{Treg|totalTau} = 0.43, p = 0.021, n = 28; r_Treg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (r_{Treg|totalTau} ₌ −0.51, p = 0.007, n = 26). The increase of circulating CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells in the early stages of AD and the association of CD4⁺CD127^lowCD25⁺ T_regs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.</p

image_1_Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study.tif

<p>The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (T_h) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCI_AD, n = 14), with MCI unlikely due to AD (MCI_other, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells, CD3⁺CD8⁻IL-17A⁻IFNγ⁺ Th1 cells, and CD4⁺CD127^lowCD25⁺ regulatory T cells (T_regs) were assessed by flow cytometry. In addition, the correlations of the proportions of T_h subsets to cerebrospinal fluid biomarkers were studied. CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells were significantly increased in subjects with MCI_AD compared to age- and sex-matched subjects with MCI_other and controls (MCI_AD mean = 1.13, SD = 0.77; MCI_other mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4⁺CD127^lowCD25⁺ T_regs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (r_{Treg|totalTau} = 0.43, p = 0.021, n = 28; r_Treg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (r_{Treg|totalTau} ₌ −0.51, p = 0.007, n = 26). The increase of circulating CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells in the early stages of AD and the association of CD4⁺CD127^lowCD25⁺ T_regs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.</p

image_3_Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study.tif

<p>The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (T_h) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCI_AD, n = 14), with MCI unlikely due to AD (MCI_other, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells, CD3⁺CD8⁻IL-17A⁻IFNγ⁺ Th1 cells, and CD4⁺CD127^lowCD25⁺ regulatory T cells (T_regs) were assessed by flow cytometry. In addition, the correlations of the proportions of T_h subsets to cerebrospinal fluid biomarkers were studied. CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells were significantly increased in subjects with MCI_AD compared to age- and sex-matched subjects with MCI_other and controls (MCI_AD mean = 1.13, SD = 0.77; MCI_other mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4⁺CD127^lowCD25⁺ T_regs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (r_{Treg|totalTau} = 0.43, p = 0.021, n = 28; r_Treg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (r_{Treg|totalTau} ₌ −0.51, p = 0.007, n = 26). The increase of circulating CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells in the early stages of AD and the association of CD4⁺CD127^lowCD25⁺ T_regs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.</p

table_1_Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study.xls

<p>The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (T_h) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCI_AD, n = 14), with MCI unlikely due to AD (MCI_other, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells, CD3⁺CD8⁻IL-17A⁻IFNγ⁺ Th1 cells, and CD4⁺CD127^lowCD25⁺ regulatory T cells (T_regs) were assessed by flow cytometry. In addition, the correlations of the proportions of T_h subsets to cerebrospinal fluid biomarkers were studied. CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells were significantly increased in subjects with MCI_AD compared to age- and sex-matched subjects with MCI_other and controls (MCI_AD mean = 1.13, SD = 0.77; MCI_other mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4⁺CD127^lowCD25⁺ T_regs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (r_{Treg|totalTau} = 0.43, p = 0.021, n = 28; r_Treg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (r_{Treg|totalTau} ₌ −0.51, p = 0.007, n = 26). The increase of circulating CD3⁺CD8⁻IL-17A⁺IFNγ⁻ Th17 cells in the early stages of AD and the association of CD4⁺CD127^lowCD25⁺ T_regs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.</p