Stefan Bräse

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics

The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has given rise to more dangerous strains of bacteria. An understanding of the chemistry and biology of these highly complex glycopeptides are destined to play a crucial role in the discovery of new antibiotics.

Recent approaches towards the asymmetric synthesis of α,α-disubstituted α-amino acids

The class of alpha,alpha-disubstituted alpha-amino acids has gained considerable attention in the past decades and continues doing so. The ongoing interest in biological and chemical properties of the substance class has inspired the development of many new methodologies for their asymmetric construction, which have not found their way into the general focus of organic chemistry yet. The aim of this review is to provide an overview of the developments in the field since 1998.

Synthesis, structure, and characterization of dinuclear copper(I) halide complexes with P^N ligands featuring exciting photoluminescence properties.

A series of highly luminescent dinuclear copper(I) complexes has been synthesized in good yields using a modular ligand system of easily accessible diphenylphosphinopyridine-type P^N ligands. Characterization of these complexes via X-ray crystallographic studies and elemental analysis revealed a dinuclear complex structure with a butterfly-shaped metal-halide core. The complexes feature emission covering the visible spectrum from blue to red together with high quantum yields up to 96%. Density functional theory calculations show that the HOMO consists mainly of orbitals of both the metal core and the bridging halides, while the LUMO resides dominantly on the heterocyclic part of the P^N ligands. Therefore, modification of the heterocyclic moiety of the bridging ligand allows for systematic tuning of the luminescence wavelength. By increasing the aromatic system of the N-heterocycle or through functionalization of the pyridyl moiety, complexes with emission maxima from 481 to 713 nm are obtained. For a representative compound, it is shown that the ambient-temperature emission can be assigned as a thermally activated delayed fluorescence, featuring an attractively short emission decay time of only 6.5 μs at ϕPL = 0.8. It is proposed to apply these compounds for singlet harvesting in OLEDs.

The Recent Impact of Solid-Phase Synthesis on Medicinally Relevant Benzoannelated Nitrogen Heterocycles

Benzoannelated heterocycles such as benzodiazepines and indoles can be prepared efficiently through cyclization on solid supports, although no single approach is currently universal for the preparation of all benzoannelated N-heterocycle chemistries. In this review, a number of synthetic strategies for the generation of benzoannelated nitrogen heterocycles using resin-bound substrates have been described. Classical heterocycle forming reactions such as the Fischer indole, the Bischler-Napieralski tetrahydroisoquinoline, the Pictet-Spengler tetrahydro-beta-carboline, the Tsuge, the Nenitzescu and the Richter cinnoline reaction are presented. In addition, the Heck, Sonogashira, Wittig, Diels-Alder, and olefin metathesis reactions have been also used. Multicomponent reactions such as the Grieco three-component assembly have been exploited for the synthesis of heterocycles. Cyclative cleavage from the solid support is particularly suitable for the synthesis of heterocycles while particular emphasis has been focused on the synthesis of libraries and the use of combinatorial chemistry techniques. In addition, the most relevant pharmacological properties of benzoannelated nitrogen heterocycles are included.

Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons.

Cell surface proteolysis is essential for communication between cells and results in the shedding of membrane‐protein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome‐wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry‐mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates—seizure‐protein 6, L1, CHL1 and contactin‐2—were validated in brains of BACE1 inhibitor‐treated and BACE1 knock‐out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells.

Secretome Protein Enrichment with Click Sugars Identifies Physiological Substrates of the Alzheimer Protease BACE1 in Primary Neurons

Cell surface proteolysis is essential for communication between cells and results in the shedding of membrane‐protein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome‐wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry‐mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates—seizure‐protein 6, L1, CHL1 and contactin‐2—were validated in brains of BACE1 inhibitor‐treated and BACE1 knock‐out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells.

Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

Ortho-trifluoromethylation of functionalized aromatic triazenes.

Fluorine containing organic agents play a crucial role in the search for new active pharmaceutical and agrochemical compounds. Owing to their fluorine moieties, these compounds have unique chemical and physical properties. For example, they can increase the metabolic stability or the lipophilicity, which can enhance the biological activity of a drug. For these reasons, the CF3 group is an essential moiety of numerous commercially available aromatic and non-aromatic biological active agents. Therefore, the research on new

Enantioselective Intramolecular Friedel−Crafts-Type α-Arylation of Aldehydes

Enantioselective organo-SOMO catalysis has, in the last two years, been the subject of considerable development and exploration. A number of new and unique transformations have been reported, such as alpha-allylation, alpha-oxyamination, alpha-enolation, and alpha-vinylation of aldehydes. Herein, we report a modification of this activation mode that involves the intramolecular Friedel-Crafts-type alpha-arylation of aldehydes carrying electron-donating groups on their aromatic nucleus and its application to the total synthesis of demethyl calamenene, a potent cytotoxic agent against human adenocarcinoma A 549.

Chemie, Biologie und medizinische Anwendungen der Glycopeptid‐Antibiotika

Der Krieg gegen pathogene Bakterien ist noch nicht vorbei! Zwar bilden Vancomycin und andere Glycopeptid-Antibiotika eine letzte Verteidigungslinie gegen zahlreiche mehrfachresistente Bakterien, doch ihr leichtfertiger Gebrauch hat zur Bildung etlicher gefahrlicherer Bakterienstamme gefuhrt. Das Verstandnis der chemischen und biologischen Eigenschaften dieser hochkomplexen Glycopeptide durfte eine entscheidende Rolle fur die Entdeckung und Entwicklung neuer Antibiotika spielen.