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Die eingereichte Dissertation liefert fundamentale Erkenntnisse zur Chemie nucleophiler Borzentren, die unter B•B-, B–B- und B=B-Bindungsbildungen reagieren. Zusammen mit den aufgedeckten Prinzipien zu (e–)-induzierten Umlagerungen des 9-Borafluorengrundgerüsts und Übertragungen von Hydridionen liegt nun ein umfassendes mechanistisches Wissen vor, das die effiziente Synthese neuartiger Moleküle ermöglicht. Im Folgenden ist eine Übersicht über bearbeitete Teilprojekte gegeben.
Durch Reduktion des Bis(9-borafluorenyl)methans 7 wurde über [7•]– (B•B-Einelektron-Zweizentrenbindung) und [7]2– (B–B-Zweielektronen-Zweizentrenbindung) das Tetraanion [7]4– dargestellt, das bei Zugabe von Elektrophilen unter Oxidation reagiert.
Die Injektion von Elektronen in das B(µ-H)2B dotierte Dibenzo[g,p]chrysen 12 führt in Abhängigkeit der Natur und der Stöchiometrie des eingesetzten Reduktionsmittels zu unterschiedlichen Hauptprodukten (bordotierte Dibenzo[g,p]chrysen- oder 9,9‘-Bifluorenylgrundkörper) mit verschiedenen Bindungsmodi (B–B-, B=B- oder (µ-H)B-B-Bindungen), deren Entstehung mechanistisch über Gerüstumlagerungen und Hydridübertragungen dargelegt wurde.
Durch die Zugabe etherischer HCl kann die B=B-Bindung in [37]2– quantitativ zu [116]– [(µ-H)B–B] oder 12 (B(µ-H)2B) protoniert werden. Umgekehrt lässt sich das scheinbar hydridische Diboran 12 durch sterisch anspruchsvolle Basen selektiv zu [116]– deprotonieren. Die kleine Base H3CLi führt neben der Deprotonierung von 12 auch zu einem Bis(9-borafluorenyl)methan, das ein verbrückendes Hydridion trägt ([125]–). Der Mechanismus wurde detailliert untersucht (z. B. wurde eine C–H-Aktivierung aufgeklärt), was u. a. genutzt werden konnte, um einen atomökonomischen Pfad von [37]2– zu [125]– zu etablieren.
Die Intermediate [132Cn,X]– (formale Addukte eines 9-Borafluorenyl-Anions an borständig substituierte 9-Borafluorene), gebildet durch die Zugabe von Halogenalkanen zu [37]2–, reagieren in Abhängigkeit der borständigen Alkylkette unter: (i) intramolekularer C–H-Aktivierung, (ii) intramolekularer Substitutionen oder (iii) intermolekularer Substitution.
Die Reduktion des 9-Borafluorens 6∙THF mit Lithium erzeugt das B=B-gebundene Dibenzo[g,p]chrysen-Dianion [37]2–, das 9-Borafluoren-Dianion [6]2–, das 9,9-Dihydroboratafluoren [34]– und das tetraanionische Bis(9-borafluorenyl) [146]4–.
Das 9-Borafluoren-Dianion [6]2–, das durch Reduktion von 6∙THF bei –78 °C mit Alkalimetallen selektiv dargestellt wurde, reagiert als formales Nucleophil. Über eine Reaktionskaskade gelang die selektive Synthese unterschiedlicher Produkte, die bei der literaturbekannten Reduktion des unsymmetrischen 9-Borafluoren-Dimers (6)2 mit Lithium in Toluol in Gegenwart von Et3SiBr beschrieben wurden. Hierüber konnte u. a. die Bildung eines organischen Derivats von [B3H8]– erklärt werden.
[Nachruf] Hugo Fasold
(2018)
Two subvalent, redox-active diborane(4) anions, [3]4− and [3]2−, carrying exceptionally high negative charge densities are reported: Reduction of 9-methoxy-9-borafluorene with Li granules without stirring leads to the crystallization of the B(sp3)−B(sp2) diborane(5) anion salt Li[5]. [5]− contains a 2,2′-biphenyldiyl-bridged B−B core, a chelating 2,2′-biphenyldiyl moiety, and a MeO substituent. Reduction of Li[5] with Na metal gives the Na+ salt of the tetraanion [3]4− in which two doubly reduced 9-borafluorenyl fragments are linked via a B−B single bond. Comproportionation of Li[5] and Na4[3] quantitatively furnishes the diborane(4) dianion salt Na2[3], the doubly boron-doped congener of 9,9′-bis(fluorenylidene). Under acid catalysis, Na2[3] undergoes a formal Stone–Wales rearrangement to yield a dibenzo[g,p]chrysene derivative with B=B core. Na2[3] shows boron-centered nucleophilicity toward n-butyl chloride. Na4[3] produces bright blue chemiluminescence when exposed to air.
Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target coverage advocating the combined use of data from multiple sources. Using data from ChEMBL, PubChem, IUPHAR/BPS, BindingDB, and Probes & Drugs, we assembled a consensus dataset focusing on small molecules with bioactivity on human macromolecular targets. This allowed an improved coverage of compound space and targets, and an automated comparison and curation of structural and bioactivity data to reveal potentially erroneous entries and increase confidence. The consensus dataset comprised of more than 1.1 million compounds with over 10.9 million bioactivity data points with annotations on assay type and bioactivity confidence, providing a useful ensemble for computational applications in drug design and chemogenomics.
Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.
Organ-on-a-chip technology has the potential to accelerate pharmaceutical drug development, improve the clinical translation of basic research, and provide personalized intervention strategies. In the last decade, big pharma has engaged in many academic research cooperations to develop organ-on-a-chip systems for future drug discoveries. Although most organ-on-a-chip systems present proof-of-concept studies, miniaturized organ systems still need to demonstrate translational relevance and predictive power in clinical and pharmaceutical settings. This review explores whether microfluidic technology succeeded in paving the way for developing physiologically relevant human in vitro models for pharmacology and toxicology in biomedical research within the last decade. Individual organ-on-a-chip systems are discussed, focusing on relevant applications and highlighting their ability to tackle current challenges in pharmacological research.
Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It is established that the activation of PLK1 depends on the coordinated action of Aurora-A and Bora. Nevertheless, very little is known about the spatiotemporal regulation of PLK1 during G2, specifically, the mechanisms that keep cytoplasmic PLK1 inactive until shortly before mitosis onset. Here, we describe PLK1 dimerization as a new mechanism that controls PLK1 activation. During the early G2 phase, Bora supports transient PLK1 dimerization, thus fine-tuning the timely regulated activation of PLK1 and modulating its nuclear entry. At late G2, the phosphorylation of T210 by Aurora-A triggers dimer dissociation and generates active PLK1 monomers that support entry into mitosis. Interfering with this critical PLK1 dimer/monomer switch prevents the association of PLK1 with importins, limiting its nuclear shuttling, and causes nuclear PLK1 mislocalization during the G2-M transition. Our results suggest a novel conformational space for the design of a new generation of PLK1 inhibitors.
RcsF, a proposed auxiliary regulator of the regulation of capsule synthesis (rcs) phosphorelay system, is a key element for understanding the RcsC-D-A/B signaling cascade, which is responsible for the regulation of more than 100 genes and is involved in cell division, motility, biofilm formation, and virulence. The RcsC-D-A/B system is one of the most complex bacterial signal transduction pathways, consisting of several membrane-bound and soluble proteins. RcsF is a lipoprotein attached to the outer membrane and plays an important role in activating the RcsC-d-A/B pathway. The exact mechanism of activation of the rcs phosphorelay by RcsF, however, remains unknown. We have analyzed the sequence of RcsF and identified three structural elements: 1) an N-terminal membrane-anchored helix (residues 3-13), 2) a loop (residues 14-48), and 3) a C-terminal folded domain (residues 49-134). We have determined the structure of this C-terminal domain and started to investigate its interaction with potential partners. Important features of its structure are two disulfide bridges between Cys-74 and Cys-118 and between Cys-109 and Cys-124. To evaluate the importance of this RcsF disulfide bridge network in vivo, we have examined the ability of the full-length protein and of specific Cys mutants to initiate the rcs signaling cascade. The results indicate that the Cys-74/Cys-118 and the Cys-109/Cys-124 residues correlate pairwise with the activity of RcsF. Interaction studies showed a weak interaction with an RNA hairpin. However, no interaction could be detected with reagents that are believed to activate the rcs phosphorelay, such as lysozyme, glucose, or Zn(2+) ions.