Aggregation Effects in Visible‐Light Flavin Photocatalysts: Synthesis,Structure, and Catalytic Activity of 10‐Arylflavins

A series of 10‐arylflavins (10‐phenyl‐, 10‐(2′,6′‐dimethylphenyl)‐, 10‐(2′,6′‐diethylphenyl)‐, 10‐(2′,6′‐diisopropylphenyl)‐, 10‐(2′‐tert‐butylphenyl)‐, and 10‐(2′,6′‐dimethylphenyl)‐3‐methylisoalloxazine ( 2 a – f )) was prepared as potentially nonaggregating flavin photocatalysts. The investigation of their structures in the crystalline phase combined with ¹H‐DOSY NMR spectroscopic experiments in CD₃CN, CD₃CN/D₂O (1:1), and D₂O confirm the decreased ability of 10‐arylflavins 2 to form aggregates relative to tetra‐O‐acetyl riboflavin ( 1 ). 10‐Arylflavins 2 a – d do not interact by π–π interactions, which are restricted by the 10‐phenyl ring oriented perpendicularly to the isoalloxazine skeleton. On the other hand, N3? H???O hydrogen bonds were detected in their crystal structures. In the structure of 10‐aryl‐3‐methylflavin ( 2 f ) with a substituted N3 position, weak C? H???O bonds and weak π–π interactions were found. 10‐Arylflavins 2 were tested as photoredox catalysts for the aerial oxidation of 4‐methoxybenzyl alcohol to the corresponding aldehyde (model reaction), thus showing higher efficiency relative to 1 . The quantum yields of 4‐methoxybenzyl alcohol oxidation reactions mediated by arylflavins 2 were higher by almost one order of magnitude relative to values in the presence of 1 .     

A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies

Anaphylaxis is a potentially life-threatening condition triggered mainly by the release of inflammatory mediators, notably histamine. In pharmaceutical research, drug discovery, and clinical evaluation, it may be necessary to accurately assess the potential of a compound, event, or disorder to promote the release of histamine. In contrast to the measurement of plasma histamine, determination of the stable metabolite 1-methyl-4-imidazoleacetic acid (tele-MIAA) in urine provides a noninvasive and more reliable methodology to monitor histamine release. This study presents a repeatable high-performance liquid chromatography coupled to electrospray mass spectrometry (LC–ESI–MS) method where tele-MIAA is baseline separated from its structural isomer 1-methyl-5-imidazoleacetic acid (pi-MIAA) and an unknown in human urine. The ion-pairing chromatography method, in reversed-phase mode, based on 0.5 mM tridecafluoroheptanoic acid demonstrated high repeatability and was applied in a clinical development program that comprised a large number of clinical samples from different cohorts. The inter- and intra-run precision of the method for tele-MIAA were 8.4 and 4.3 %, respectively, at the mean urinary concentration level, while method accuracy was between ?16.2 and 8.0 % across the linear concentration range of 22–1,111 ng mL^?1. Overall, method precision was greater than that reported in previously published methods and enabled the identification of gender differences that were independent of age or demography. The median concentration measured in female subjects was 3.0 μmol mmol^?1 of creatinine, and for male subjects, it was 2.1 μmol mmol^?1 of creatinine. The results demonstrate that the method provides unprecedented accuracy, precision, and practicality for the measurement of tele-MIAA in large clinical settings.

Detection of potentially skin sensitizing hydroperoxides of linalool in fragranced products

On prolonged exposure to air, linalool can form sensitizing hydroperoxides. Positive hydroperoxide patch tests in dermatitis patients have frequently been reported, but their relevance has not been established. Owing to a lack of analytical methods and data, it is unclear from which sources the public might be exposed to sufficient quantities of hydroperoxides for induction of sensitization to occur. To address this knowledge gap, we developed analytical methods and performed stability studies for fine fragrances and deodorants/antiperspirants. In parallel, products recalled from consumers were analysed to investigate exposure to products used in everyday life. Liquid chromatography–mass spectrometry with high mass resolution was found to be optimal for the selective and sensitive detection of the organic hydroperoxide in the complex product matrix. Linalool hydroperoxide was detected in natural linalool, but the amount was not elevated by storage in a perfume formulation exposed to air. No indication of hydroperoxide formation in fine fragrances was found in stability studies. Aged fine fragrances recalled from consumers contained a geometric mean linalool concentration of 1,888 μg/g and, corrected for matrix effects, linalool hydroperoxide at a concentration of around 14 μg/g. In antiperspirants, we detected no oxidation products. In conclusion, very low levels of linalool hydroperoxide in fragranced products may originate from raw materials, but we found no evidence for oxidation during storage of products. The levels detected are orders of magnitude below the levels inducing sensitization in experimental animals, and these results therefore do not substantiate a causal link between potential hydroperoxide formation in cosmetics and positive results of patch tests. Graphical Abstract

Formation of hydroperoxides from linalool and detection by LC-MS with high resolution     

Adamantyl Side Chains as Anti-Aggregating Moieties in Dyes for Dye-Sensitized Solar Cells

Designing and evaluating novel dye concepts is crucial for the development of the field of dye-sensitized solar cells (DSSCs). In our recent report, the novel concept of tethering the anti-aggregation additive chenodeoxycholic acid (CDCA) to dyes for DSSC was introduced. Based on the performance improvements seen for this modification, the aim of this study is to see if a simplified anti-aggregation unit could achieve similar results. The following study reports the synthesis and photovoltaic characterization of two novel dyes decorated with the steric ethyladamantyl moiety on the π-spacer, and on the triarylamine donor. This modification is demonstrated to be successful in increasing the photovoltages in devices employing copper-based electrolytes compared to the non-modified reference dye. The best photovoltaic performance is achieved by a device prepared with the adamantyl decorated donor dye and CDCA, this device achieves a power conversion efficiency of 6.1 % (Short-circuit current=8.3 mA cm⁻², Open-circuit voltage=1054 mV, Fill factor=0.69). The improved photovoltaic performance seen for the adamantyl decorated donor demonstrate the potential of ethyladamantyl side chains as a tool to ensure surface protection of TiO₂.     

Spatial and temporal resolution effects on dynamic contrast-enhanced magnetic resonance mammography

We tested the hypothesis that partial volume effects due to poor in-plane resolution and/or low temporal resolution used in clinical dynamic contrast-enhanced magnetic resonance imaging results in erroneous diagnostic information based on inaccurate estimates of tumor contrast agent extravasation and tested whether reduced encoding techniques can correct for dynamic data volume averaging. Image spatial resolution was reduced from 469 x 469 microm2 to those reported below by selecting a subset of k-space data. We then compared the top five K(trans)/V(T) "hot spots" obtained from the original data set, 469 x 469-microm in-plane spatial resolution and an 18-s temporal resolution processed by fast Fourier transform (FFT), with values obtained from data sets having in-plane spatial resolutions of 938 x 938, 1875 x 1875 and 2500 x 2500 microm2 and a temporal resolution of 18 s, or data sets with temporal resolutions of 36, 54 and 72 and a spatial resolution of 469 x 469 microm2, and found them to statistically differ from the parent data sets. We then tested four different post processing methods for improving the spatial resolution without sacrificing temporal resolution: zero-filled FFT, keyhole, reduced-encoding imaging by generalized-series reconstruction (RIGR) and two-reference RIGR (TRIGR). The top five values of K(trans)/V(T) obtained from data sets, the in-plane spatial resolutions of which were improved to 469 x 469 microm2 by zero-filling FFT, Keyhole and RIGR, statistically differed from those obtained from the original 469 x 469 microm2 FFT parent image data set. Only the 938 x 938 and 1875 x 1875 microm2 data sets reconstructed to 469 x 469 microm2 with TRIGR reconstruction method yielded values of the top five K(trans)/V(T) hot spots statistically the same as the original parent data set, 469 x 469 microm2 in-plane spatial and 18-s temporal-resolution FFT. That is, partial volume effects from data sets of different in-plane spatial resolution resulted in statistically different values of the top five K(trans)/V(T) hot spots relative to a high spatial and temporal resolution data set, and TRIGR reconstruction of these low resolution data sets to high resolution images provided statistically similar values with a savings in temporal resolution of 2 to 4 times.     

Improved CE(SDS)-CZE-MS method utilizing an 8-port nanoliter valve

Capillary sieving electrophoresis utilizing SDS (CE(SDS)) is one of the most applied methods for the analysis of antibody (mAb) size heterogeneity in the biopharmaceutical industry. Inadequate peak identification of observed protein fragments is still a major issue. In a recent publication, we introduced an electrophoretic 2D system, enabling online mass spectrometric detection of generic CE(SDS) separated peaks and identification of several mAb fragments. However, an improvement regarding system stability and handling of the approach was desired. Here, we introduce a novel 8-port valve in conjunction with an optimized decomplexation strategy. The valve contains four sample loops with increased distances between the separation dimensions. Thus, successively coinjection of solvent and cationic surfactant without any additional detector in the second dimension is enabled, simplifying the decomplexation strategy. Removal efficiency was optimized by testing different volumes of solvents as presample and cationic surfactant as postsample zone. 2D measurements of the light and heavy chain of the reduced NIST mAb with the 8-port valve and the optimized decomplexation strategy demonstrates the increased robustness of the system. The presented novel set-up is a step toward routine application of CE(SDS)-CZE-MS for impurity characterization of proteins in the biopharmaceutical field.     

Fluorinated Azobenzenes Switchable with Red Light

Molecular photoswitches triggered with red or NIR light are optimal for photomodulation of complex biological systems, including efficient penetration of the human body for therapeutic purposes (“therapeutic window”). Yet, they are rarely reported, and even more rarely functional under aqueous conditions. In this work, fluorinated azobenzenes are shown to exhibit efficient E→Z photoisomerization with red light (PSS_660nm >75 % Z) upon conjugation with unsaturated substituents. Initially demonstrated for aldehyde groups, this effect was also observed in a more complex structure by incorporating the chromophore into a cyclic dipeptide with propensity for self-assembly. Under physiological conditions, the latter molecule formed a supramolecular material that reversibly changed its viscosity upon irradiation with red light. Our observation can lead to design of new photopharmacology agents or phototriggered materials for in vivo use.     

Determination of conditional stability constants for some divalent transition metal ion‐EDTA complexes by electrospray ionization mass spectrometry

Conditional stability constants of coordination complexes comprising divalent transition metals, Cu²⁺, Ni²⁺, Zn²⁺, Co²⁺, and ethylenediaminetetraacetic acid (EDTA) were determined utilizing electrospray ionization mass spectrometry. The deviation of signal response of a reference complex was monitored at addition of a second metal ion. The conditional stability constant for the competing metal was then determined through solution equilibria equations. The method showed to be applicable to a system where Co²⁺ and Zn²⁺ competed for EDTA at pH 5. When Cu²⁺ and Ni²⁺ competed for EDTA, the equilibrium changed over time. This change was shown to be affected in rate and size by the type of organic solvent added. In this work, 30% of either methanol or acetonitrile was used. It was found that if calibration curves are prepared for both metal complexes in solution and the measurements are repeated with sufficient time space, any change in equilibrium of sample solutions will be discovered. Copyright © 2014 John Wiley & Sons, Ltd.     

Sequence Control in Polymer Chemistry through the Passerini Three‐Component Reaction

A new strategy to achieve sequence control in polymer chemistry based on the iterative application of the versatile Passerini three‐component reaction (P‐3CR) in combination with efficient thiol–ene addition reactions is introduced. First, stearic acid was used as a starting substrate to build up a sequence‐defined tetramer with a molecular weight of 1.6 kDa. Using an acid‐functionalized PEG allowed for an easier isolation of the sequence‐defined macromolecules by simple precipitation and led to a sequence‐defined pentamer in a block‐copolymer architecture. Importantly, this new strategy completely avoids protecting group chemistry. By following this strategy, a different side chain can be introduced to the polymer/oligomer backbone in a simple way and at a defined position within the macromolecule.