Synthesis of a Bicyclic Diamine Derived from Kemp's Acid

A bicyclic diamine with defined and stable conformation in solution was prepared from Kemp's triacid. The efficient four-step synthesis of the Boc-protected diamine requires only a single purification by column chromatography. X-ray analysis and NMR spectroscopy confirm the structure of the diamine in the solid state and in solution.     

Polyelectrolyte–protein interaction at low ionic strength: required chain flexibility depending on protein average charge

The effect of low ionic strength leading to reduced polyelectrolyte–protein interactions has been shown by in silico and in vitro experiments, suggesting polyelectrolyte rigidity increasing at low ionic strength, thus leading to reduced interactions with proteins. This contribution elucidates polyelectrolyte–protein precipitation in the 0–2.6-mS?cm^?1 ionic strength regime with polyelectrolyte rigidity determinations, using viscosimetry at these conditions, also considering protein charge distributions, using different proteins. Precipitation yields increased from 5 to 40 % at low ionic strength to up to 90 % at intermediate ionic strength, depending on protein and polyelectrolyte type, using lysozyme and three different monoclonal antibodies. Comparing precipitation behavior of the monoclonal antibodies, a qualitative correlation between required polyelectrolyte flexibility to enhance protein precipitation and protein average charge as well as hydrophobicity of the antibodies was discovered. Antibodies with lower average charge and less hydrophobicity required more flexible polyelectrolytes to enhance precipitation behavior by allowing interaction of the polyelectrolytes with proteins, attaching to positively charged protein patches while “circumnavigating” negatively charged protein areas. In contrast, antibodies with higher protein average charge showed increasing precipitation yields up to 90 % already at lower ionic strength, associated with then more rigid polyelectrolyte structures. Therefore, designing polyelectrolytes with specific chain flexibility could help to improve precipitation behavior toward specific target proteins in polyelectrolyte-driven purification techniques.     

Near-Enantiopure Trimerization of 9-Ethynylphenanthrene on a Chiral Metal Surface

Enantioselectivity in heterogeneous catalysis strongly depends on the chirality transfer between catalyst surface and all reactants, intermediates, and the product along the reaction pathway. Herein we report the first enantioselective on-surface synthesis of molecular structures from an initial racemic mixture and without the need of enantiopure modifier molecules. The reaction consists of a trimerization via an unidentified bonding motif of prochiral 9-ethynylphenanthrene (9-EP) upon annealing to 500 K on the chiral Pd₃-terminated PdGa{111} surfaces into essentially enantiopure, homochiral 9-EP propellers. The observed behavior strongly contrasts the reaction of 9-EP on the chiral Pd₁-terminated PdGa{111} surfaces, where 9-EP monomers that are in nearly enantiopure configuration, dimerize without enantiomeric excess. Our findings demonstrate strong chiral recognition and a significant ensemble effect in the PdGa system, hence highlighting the huge potential of chiral intermetallic compounds for enantioselective synthesis and underlining the importance to control the catalytically active sites at the atomic level.     

Selective and Wash-Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single-Molecule Imaging of μ-Opioid Receptor Dimerization

μ-Opioid receptors (μ-ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ-ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ-OR antagonist E-p-nitrocinnamoylamino-dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single-molecule imaging of μ-ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ-ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ-ORs interact with each other to form short-lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ-OR pharmacology at single-molecule level.     

The Kolmogorov–Riesz compactness theorem

We show that the Arzelà–Ascoli theorem and Kolmogorov compactness theorem both are consequences of a simple lemma on compactness in metric spaces. Their relation to Helly's theorem is discussed. The paper contains a detailed discussion on the historical background of the Kolmogorov compactness theorem.     

Primordial <Superscript>4</Superscript>He Abundance Constrains the Possible Time Variation of the Higgs Vacuum Expectation Value

We constrain the possible time variation of the Higgs vacuum expectation value (v) by recent results on the primordial ⁴He abundance (Y _P ). For that, we use an analytic approach which enables us to take important issues into consideration, that have been ignored by previous works, like the v-dependence of the relevant cross sections of deuterium production and photodisintegration, including the full Klein–Nishina cross section. Furthermore, we take a non-equilibrium Ansatz for the freeze-out concentration of neutrons and protons and incorporate the latest results on the neutron decay. Finally, we approximate the key-parameters of the primordial ⁴He production (the mean lifetime of the free neutron and the binding energy of the deuteron) by terms of (where v ₀ denotes the present theoretical estimate). Eventually, we derive the relation and the most stringent limit on a possible time variation of v is given by: .     

Dextramabs: A Novel Format of Antibody-Drug Conjugates Featuring a Multivalent Polysaccharide Scaffold

Antibody-drug conjugates (ADCs) are multicomponent biomolecules that have emerged as a powerful tool for targeted tumor therapy. Combining specific binding of an immunoglobulin with toxic properties of a payload, they however often suffer from poor hydrophilicity when loaded with a high amount of toxins. To address these issues simultaneously, we developed dextramabs, a novel class of hybrid antibody-drug conjugates. In these architectures, the therapeutic antibody trastuzumab is equipped with a multivalent dextran polysaccharide that enables efficient loading with a potent toxin in a controllable fashion. Our modular chemoenzymatic approach provides an access to synthetic dextramabs bearing monomethyl auristatin as releasable cytotoxic cargo. They possess high drug-to-antibody ratios, remarkable hydrophilicity, and high toxicity in vitro.