TY - JOUR A1 - Braunschweig, Holger A1 - Dewhurst, Rian D. A1 - Schwab, Katrin A1 - Wagner, Katharina T1 - {N ',N ''-Bis[2,6-bis(1-methylethyl)phenyl]-N,N-dimethylguanidinato-kappa N-2 ',N ''}dibromidoborane N2 - In the molecular structure of the title compound, C27H40N3BBr2, the B atom is connected to two bromide substituents and a guanidinate scaffold, forming a four– membered ring. An aryl group is connected to each N atom in the ring that contains two isopropyl groups in positions 2 and 6. KW - Anorganische Chemie Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67622 ER - TY - THES A1 - Wagner, Katharina T1 - Synthese und Reaktivität der Lewis-Säure-Base-Addukte von Monoboranen und Diboranen(4) T1 - Synthesis and Reactivity of Lewis Acid-Base Adducts of Monoboranes and Diboranes(4) N2 - Im Rahmen dieser Arbeit wurden verschiedene Addukte von Lewis-Säuren und Lewis-Basen synthetisiert und hinsichtlich ihrer Reaktivität, vor allem gegenüber verschiedenen Reduktionsmitteln, untersucht. Als Lewis-Säuren wurden Monoborane und Diborane(4) eingesetzt. Aus der Verbindungsklasse der Monoborane wurden die Aryldihalogenborane MesBBr2 und PhBBr2 untersucht, da diese durch ihre zwei Halogene und ihren sterisch anspruchsvollen Arylrest möglicherweise zu niedervalenten Borverbindungen führen. In der Verbindungsklasse der Diborane(4) wurden B2Cl2Mes2, B2Br2Mes2 und B2I2Mes2 für die Synthese von Addukten verwendet. Aus der Umsetzung von ArBBr2 (Ar = Mes und Ph) mit SIMes erhält man die Monoboran-NHC-Addukte MesBBr2•SIMes und PhBBr2•SIMes. Beide Verbindungen sind farblose Feststoffe und zeigen im 11B-NMR-Spektrum ein Signal im erwarteten Bereich bei ca. –5 ppm. Die erhaltenen Signale im 1H-NMR Spektrum lassen sich den entsprechenden Protonen zuordnen und die Integrale stimmen mit der Anzahl der Protonen überein. Beide Verbindungen sind schlecht löslich, daher konnten keine Einkristalle für eine nähere Strukturbestimmung erhalten werden. In der vorliegenden Arbeit konnte gezeigt werden, dass nicht nur Monoborane mit NHCs 1:1-Addukte bilden, auch Diborane(4) können erfolgreich mit Phosphanen umgesetzt werden. Darüber hinaus konnten die Strukturen der beiden Verbindungen B2Cl2Mes2•PMe3 und B2Br2Mes2•PMe3 mit Hilfe einer Einkristallstrukturanalyse aufgeklärt werden. Durch die Koordination von PMe3 an einem Boratom, erhöht sich an diesem die Elektronendichte. Dies erkennt man z. B. in beiden Verbindungen an den längeren B –Halogen-Bindungen im Vergleich zum Edukt B2X2Mes2. Zudem ist das am vierfach-koordinierten Boratom gebundene Halogen in beiden Fällen deutlich zum dreifach-koordinierten Boratom geneigt. Dies kann man aus den erhaltenen Bindungswinkeln schließen. Nicht nur Trimethylphosphan reagiert mit Diboranen(4) zu 1:1-Addukten, auch N-Heterocyclische Carbene konnten erfolgreich mit Diboranen(4) umgesetzt werden. Die beiden Addukte B2Cl2Mes2•IMe und B2Br2Mes2•IMe konnten als farblose Feststoffe isoliert werden und mit Hilfe der 11B-NMR-Spektroskopie charakterisiert werden. Beide zeigen, wie auch alle weiteren dargestellten Diboran(4)-NHC-Addukte, ein breites Signal (87.7 ppm und 76.2 ppm) für das dreifachkoordinierte Boratom und ein Signal (–4 ppm und –3.5 ppm) für das vierfachkoordinierte Boratom. Verwendet man als Carben das deutlich sterisch anspruchsvollere IDipp, erhält man in einer Ausbeute von 41% bei der Umsetzung bei tiefen Temperaturen einen farblosen Feststoff von B2Cl2Mes2•IDipp als Produkt. Die erhaltene Verbindung B2Cl2Mes2•IDipp konnte mittels 1H-, 11B- und 13C-NMR-Spektroskopie und Elementaranalyse charakterisiert werden. Die so erhaltenen Daten konnten jedoch keine endgültige Aussage über die Konnektivität der einzelnen Atome liefern. Die genaue Molekülstruktur konnte mit Hilfe der Röntgenkristallographie aufgeklärt werden. Überraschenderweise handelt es sich bei dem Produkt nicht um das einfache 1:1-Addukt der beiden Edukte. Vielmehr sind nun beide Chloratome an dem Boratom gebunden, welches zusätzlich das NHC trägt. Entsprechend trägt das dreifach-substituierte Boratom beide Mesitylsubstituenten. Somit müssen im Laufe der Reaktion eine B –Cl- und eine B –C-Bindung gebrochen worden, eine 1,2-Arylverschiebung sowie eine 1,2-Halogenverschiebung erfolgt sein. Dies konnte zuvor bei den Diboran(4)-PMe3-Addukten nicht beobachtet werden. Die Verbindung B2Cl2Mes2•IDipp zeigt mit einer B–B-Bindungslänge von 1.758(2)Å einen deutlich längeren Abstand als im Edukt. Die drei Diboran(4)-NHC-Addukte B2Br2Mes2•IMes, B2Cl2Mes2•SIMes und B2Br2Mes2•SIMes konnten erfolgreich dargestellt werden. Alle Verbindungen wurden mit Hilfe von 1H-, 11B- und 13C-NMR-Spektroskopie und Elementaranalyse charakterisiert. Zusätzlich konnten für die beiden Verbindungen B2Cl2Mes2•SIMes und B2Br2Mes2•SIMes Einkristalle erhalten werden und eine Röntgenstrukturanalyse durchgeführt werden. Bei der Reduktion von B2Cl2Mes2•SIMes mit KC8 konnte ein interessantes Produkt erhalten werden, in dem die beiden Halogene nicht mehr vorhanden sind und sich ein Fünfring gebildet hat, der beide Boratome beinhaltet. Wahrscheinlich entsteht bei der Reaktion zu 13 ein „borylenartiger“ Übergangszustand. Bemerkenswert ist außerdem, dass das NHC-stabilisierte Boratom noch ein vermuteter Übergangszustand. Proton trägt. Die Verbindung 13 wurde mittels NMR-Spektroskopie, Elementaranalyse und Röntgenstrukturanalyse vollständig charakterisiert. Bei der Messung eines 11B,1H-HMQC-NMR-Korrelationsspektrums lag die intensivste Kopplung bei der Mischzeit τ mit einer Kopplungskonstante von JBH = 160Hz. Daraus kann man schließen, dass das Bor-gebundene Proton in der Verbindung 13 in Lösung terminal gebunden ist. N2 - In the course of this work a range of Lewis acid-base adducts were prepared and their reactivity, especially towards reducing agents, was investigated. Monoboranes and diboranes(4) were used as Lewis acids. In the role of monoboranes the aryldihalogenboranes MesBBr2 and PhBBr2 were investigated. These compounds are very interesting due to the two halogens and the sterically demanding aryl groups which may allow the stabilization of low-valent boron species. From the reaction of ArBBr2 (Ar = Mes, Ph) with SIMes the monoborane-NHC adducts MesBBr2•SIMes and PhBBr2•SIMes were obtained. Both compounds are colourless solids and show a signal at ca. –5 ppm in the 11B NMR spectrum, which is in the estimated range. The respective signals in the 1H NMR spectrum can be assigned to the corresponding protons and the integrals are in good agreement with the number of protons. The solubility of the two compounds is not good, so it was not possible to grow crystals for a structure determination by X-ray. The obtained monoborane-NHC adducts MesBBr2•SIMes und PhBBr2•SIMes react in the presence of reductants. This is observable by the appearance of new signals in the 11B NMR spectrum and the colour change of the reaction solution. However, the produced compound could neither be isolated nor further characterized. The present work shows that not only monoboranes react with NHCs to build 1:1 adducts, but also that diboranes(4) can react successfully with phosphines. Furthermore, the solid state molecular structures of B2Cl2Mes2•PMe3 (3) and B2Br2Mes2•PMe3 (4) were ascertained by X-ray diffraction. From these analyses, B–B distances of 1.721(3)Å (3) and 1.719(3)Å (4) could be determined, respectively. Due to the coordination of PMe3 to one of the boron atoms, the electron density increases. This is reflected by elongated B –halogen bonds for both compounds compared to the precursors B2X2Mes2. In addition, the halogen which is bound to the fourfold coordinated boron atom in both cases is inclined towards the threefold coordinated boron atom. This circumstance can be deduced from the bonding angles. Not only trimethylphosphine reacts successfully with diboranes(4) to form 1:1 adducts, but also N-heterocyclic carbenes. The two adducts B2Cl2Mes2•IMe and B2Br2Mes2•IMe were isolated as colourless solids and were characterized by 11B NMR spectroscopy. Both compounds show, as do all following diborane(4)-NHC adducts, a broad signal (87.7 ppm and 76.2 ppm for the threefold coordinated boron atom and a signal for the fourfold coordinated boron atom (–4 ppm and –3.5 ppm). Usage of the considerably sterically demanding carbene IDipp in the reaction at low temperatures leads to a colourless solid of B2Cl2Mes2•IDipp in a yield of 41%. The product was characterised by 1H, 11B and 13C NMR spectroscopy and elemental analysis. The data gained from these analyses was insufficient to clarify the final connectivity of the compound. The molecular structure was instead ascertained by X-ray crystallography. To our surprise the product is not just a simple 1:1 adduct of the precursors. Both chlorine atoms are bound to the boron atom that is stabilised by the NHC. Accordingly, both mesityl groups are bound to the threefold coordinated boron atom. Hence, one B –Cl and one B –C bond were cleaved during the reaction and a 1,2-aryl shift and a 1,2-halogen shift have taken place. This had not been observed before in the formation of diborane(4)-PMe3 adducts. The product B2Cl2Mes2•IDipp shows a B –B bond length of 1.758(2)Å which is considerably longer than in the starting material. B2Br2Mes2 IMes, B2Cl2Mes2•SIMes and B2Br2Mes2•SIMes were successfully synthesised. All three compounds were characterised via 1H, 11B and 13C NMR spectroscopy and elemental analysis. By reduction of B2Cl2Mes2•SIMes with KC8 a highly interesting product was obtained. The product does no longer contain any halogen atoms and a five-membered ring including both boron atoms was formed. A “borylene-like“ transition state presumably occurs in the reaction to form 13. It is remarkable that in this compound the boron atom stabilised by the NHC bears also a proton. The compound 13 was completely characterised via NMR spectroscopy, elemental analysis and X-ray diffraction. During the measurement of an 11B 1H HMQC NMR correlation spectrum for the compound 13 the most intense coupling was detected at 160Hz. This results in the conclusion that the boron-bound proton is coordinated terminally in solution. KW - Diborane KW - Lewis-Säure KW - Lewis-Base KW - Heterocyclische Carbene-N KW - Diborane(4) KW - NHC KW - Borylen KW - Bor KW - Carbene KW - Reduktion KW - diboranes(4) KW - NHC KW - Lewis acid KW - Lewis base KW - borylene Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78603 ER - TY - JOUR A1 - Hebestreit, Helge A1 - Zeidler, Cornelia A1 - Schippers, Christopher A1 - de Zwaan, Martina A1 - Deckert, Jürgen A1 - Heuschmann, Peter A1 - Krauth, Christian A1 - Bullinger, Monika A1 - Berger, Alexandra A1 - Berneburg, Mark A1 - Brandstetter, Lilly A1 - Deibele, Anna A1 - Dieris-Hirche, Jan A1 - Graessner, Holm A1 - Gündel, Harald A1 - Herpertz, Stephan A1 - Heuft, Gereon A1 - Lapstich, Anne-Marie A1 - Lücke, Thomas A1 - Maisch, Tim A1 - Mundlos, Christine A1 - Petermann-Meyer, Andrea A1 - Müller, Susanne A1 - Ott, Stephan A1 - Pfister, Lisa A1 - Quitmann, Julia A1 - Romanos, Marcel A1 - Rutsch, Frank A1 - Schaubert, Kristina A1 - Schubert, Katharina A1 - Schulz, Jörg B. A1 - Schweiger, Susann A1 - Tüscher, Oliver A1 - Ungethüm, Kathrin A1 - Wagner, Thomas O. F. A1 - Haas, Kirsten T1 - Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study JF - Orphanet Journal of Rare Diseases N2 - Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. KW - rare diseases KW - multi‑center cohort study KW - dual guidance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300440 VL - 17 IS - 1 ER - TY - JOUR A1 - Janz, Anna A1 - Walz, Katharina A1 - Cirnu, Alexandra A1 - Surjanto, Jessica A1 - Urlaub, Daniela A1 - Leskien, Miriam A1 - Kohlhaas, Michael A1 - Nickel, Alexander A1 - Brand, Theresa A1 - Nose, Naoko A1 - Wörsdörfer, Philipp A1 - Wagner, Nicole A1 - Higuchi, Takahiro A1 - Maack, Christoph A1 - Dudek, Jan A1 - Lorenz, Kristina A1 - Klopocki, Eva A1 - Ergün, Süleyman A1 - Duff, Henry J. A1 - Gerull, Brenda T1 - Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes JF - Molecular Metabolism N2 - Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy. KW - cell biology KW - molecular biology KW - dilated cardiomyopathy with ataxia KW - genetics KW - metabolism KW - mitochondria KW - OXPHOS KW - ROS KW - contractility Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350393 SN - 2212-8778 VL - 79 ER -