Exploring contrast-enhancing staining agents for studying adipose tissue through contrast-enhanced computed tomography.

Contrast-enhanced computed tomography offers a nondestructive approach to studying adipose tissue in 3D. Several contrast-enhancing staining agents (CESAs) have been explored, whereof osmium tetroxide (OsO4) is the most popular nowadays. However, due to the toxicity and volatility of the conventional OsO4, alternative CESAs with similar staining properties were desired. Hf-WD 1:2 POM and Hexabrix have proven effective for structural analysis of adipocytes using contrast-enhanced computed tomography but fail to provide chemical information. This study introduces isotonic Lugol's iodine (IL) as an alternative CESA for adipose tissue analysis, comparing its staining potential with Hf-WD 1:2 POM and Hexabrix in murine caudal vertebrae and bovine muscle tissue strips. Single and sequential staining protocols were compared to assess the maximization of information extraction from each sample. The study investigated interactions, distribution, and reactivity of iodine species towards biomolecules using simplified model systems and assesses the potential of the CESA to provide chemical information. (Bio)chemical analyses on whole tissues revealed that differences in adipocyte gray values post-IL staining were associated with chemical distinctions between bovine muscle tissue and murine caudal vertebrae. More specific, a difference in the degree of unsaturation of fatty acids was identified as a likely contributor, though not the sole determinant of gray value differences. This research sheds light on the potential of IL as a CESA, offering both structural and chemical insights into adipose tissue composition.

Perfluorooxosulfate Salts as SOF4-Gas-Free Precursors to Multidimensional SuFEx Electrophiles.

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make 'beyond-linear' clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

De-Risking S-F Bond Formation: A Gas Cylinder-Free Strategy to Access S(IV) and S(VI) Fluorinated Compounds.

The sulfur-fluorine partnership occupies a privileged position in fluorine chemistry given the functional versatility that it imparts to organic structures. Despite this, available methodologies to forge S-F bonds are limited compared to C-F bond formation. Here, we describe a synthetic protocol that selectively enables the oxidative halogenation of aliphatic, aromatic, and heteroaromatic thiols to their corresponding SF4 Cl, SO2 F and SF3 derivatives. Selective oxidation of thiols to either S(IV)-F or S(VI)-F compounds is achieved by employing bench-stable calcium hypochlorite as chlorine surrogate (CLOgen), in the presence of KF as fluoride source. Density functional theory (DFT) calculations provided insight into the mechanistic aspects of the transformation and rationalized the observed isomeric preference towards the SF4 Cl derivatives. Ultimately, this glovebox-free method selectively dispatches three classes of compounds upon reaction condition fine-tuning. Furthermore, first-in-class transformations are reported, including the preparation of aliphatic SF4 Cl intermediates, their transformation into aliphatic sulfur pentafluoride analogs, and post-functionalizations that allow accessing highly complex SF4 -bridged scaffolds.

Charge transport in highly acidic glass-forming protic ionic liquids tailored by zwitterionic precursors.

Highly acidic protic ionic liquids (PILs) are promising materials for potential electrochemical applications due to their high proton conductivity and excellent thermal stability. Still, little is known about the correlation between charge transport and structural dynamics as well as the proton transport mechanism despite the large body of literature on this topic. Here, we have examined the charge transport and structural dynamics by employing broadband dielectric spectroscopy in two highly acidic PILs in their supercooled liquid and glassy states, which included the same anion [TfO]- and different cations, [Tau]+ vs [Ahs]+. Unlike many other ionic liquids, the conductivity relaxation time τe of two studied PILs is substantially faster than the structural relaxation time τα. The decoupling behavior between charge transport and structural dynamics of two materials, which is manifested by a decoupling index Rτ, varies between 0.3 and 2.3 over the temperature range above Tg. Moreover, "Walden" plots of the molar conductivity vs the viscosity qualify both compounds as "Super ILs." All findings support the physical picture of large, polar, and orientationally correlated ion clusters, where the slow α-relaxation can be identified as structural relaxation associated with cooperative reorientations of the cluster macrodipole. In contrast, the shortest timescale for diffusive charge transport, τe, is 1-2 decades shorter than τα, implying that proton hopping is triggered by "single particle" (ions or ion pair) rotations and jumps on a sub-length scale of the cluster size, a dynamics being present even in the glassy state as indicated by a strong ß-relaxation. These results demonstrate the practicality of employing highly acidic PILs in electrochemical fields.

Ex situ Generation of Thiazyl Trifluoride (NSF3 ) as a Gaseous SuFEx Hub.

Sulfur(VI)-fluoride exchange (SuFEx) chemistry, an all-encompassing term for substitution events that replace fluoride at an electrophilic sulfur(VI), enables the rapid and flexible assembly of linkages around a SVI core. Although a myriad of nucleophiles and applications works very well with the SuFEx concept, the electrophile design has remained largely SO2 -based. Here, we introduce S≡N-based fluorosulfur(VI) reagents to the realm of SuFEx chemistry. Thiazyl trifluoride (NSF3 ) gas is shown to serve as an excellent parent compound and SuFEx hub to efficiently synthesize mono- and disubstituted fluorothiazynes in an ex situ generation workflow. Gaseous NSF3 was evolved from commercial reagents in a nearly quantitative fashion at ambient conditions. Moreover, the mono-substituted thiazynes could be extended further as SuFEx handles and be engaged in the synthesis of unsymmetrically disubstituted thiazynes. These results provide valuable insights into the versatility of these understudied sulfur functionalities paving the way for future applications.

Polyketide Synthase-Mediated O-Methyloxime Formation in the Biosynthesis of the Oximidine Anticancer Agents.

Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is responsible for the biosynthesis of the oximidine anticancer agents, oxime-substituted benzolactone enamides that inhibit vacuolar H+ -ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O-methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans-AT PKSs and identify potential strategies for the production of novel oximidine analogues.

Chemistry of Pentafluorosulfanyl Derivatives and Related Analogs: From Synthesis to Applications.

Pentafluorosulfanyl (SF5 )-containing compounds and corresponding analogs are a highly valuable class of fluorine-containing building blocks owing to their unique properties. The reason for that is the set of peculiar and tremendously beneficial characteristics they can impart on molecules once introduced onto them. Despite this, their application in distinct scientific fields remains modest, given the extremely harsh reaction conditions needed to access such compounds. The recent synthetic approaches via S-F, and C-SF5 bond formation as well as the use of SF5 -containing building blocks embody a "stairway-to-heaven" loophole in the synthesis of otherwise-inaccessible chemical scaffolds only a few years ago. Herein, we report and evaluate the properties of the SF5 group and analogs, by summarizing synthetic methodologies available to access them as well as following applications in material science and medicinal chemistry since 2015.

Lighting Up the Plasma Membrane: Development and Applications of Fluorescent Ligands for Transmembrane Proteins.

Despite the fact that transmembrane proteins represent the main therapeutic targets for decades, complete and in-depth knowledge about their biochemical and pharmacological profiling is not fully available. In this regard, target-tailored small-molecule fluorescent ligands are a viable approach to fill in the missing pieces of the puzzle. Such tools, coupled with the ability of high-precision optical techniques to image with an unprecedented resolution at a single-molecule level, helped unraveling many of the conundrums related to plasma proteins' life-cycle and druggability. Herein, we review the recent progress made during the last two decades in fluorescent ligand design and potential applications in fluorescence microscopy of voltage-gated ion channels, ligand-gated ion channels and G-coupled protein receptors.

LSA-50 paper: An alternative to P81 phosphocellulose paper for radiometric protein kinase assays.

Radiometric assays have widely been used for measuring protein kinase activity for decades. In addition, several non-radiometric kinase assay formats have been developed over the years, including luciferase-based and fluorescence-based assays. However, radiometric assays are still considered as the "gold standard" for protein kinase assays, because of their direct readout, high sensitivity, reproducibility, reliability, and very low background signals. These radiometric assays rely on P81 phosphocellulose paper to capture the phosphorylated substrate and wash out unreacted [γ-32P] ATP. However, recently the production of P81 was discontinued by the manufacturer, causing major concern within the protein kinase research community. The advantages of radiometric assays over other kinase assay methods call for an urgent alternative to the discontinued P81 paper. In this report, we demonstrate that the LSA-50 paper is a worthy alternative for radiometric protein kinase assays originally using P81 phosphocellulose paper.

Solvent-free N-Boc deprotection by ex situ generation of hydrogen chloride gas.

An efficient, scalable and sustainable method for the quantitative deprotection of the tert-butyl carbamate (N-Boc) protecting group is described, using down to near-stoichiometric amounts of hydrogen chloride gas in solvent-free conditions. We demonstrate the ex situ generation of hydrogen chloride gas from sodium chloride and sulfuric acid in a two-chamber reactor, introducing a straightforward method for controlled and stoichiometric release of HCl gas. The solvent-free conditions allow deprotection of a wide variety of N-Boc derivatives to obtain the hydrochloride salts in quantitative yields. The procedure obviates the need for any work-up or purification steps providing an uncomplicated green alternative to standard methods. Due to the solvent-free, anhydrous conditions, this method shows high tolerance towards acid sensitive functional groups and furnishes expanded functional group orthogonality.

Concomitant positive patch test reactions in FreeStyle-allergic patients sensitized to isobornyl acrylate.

BACKGROUND: Concomitant positive patch test reactions in patients sensitized to isobornyl acrylate (IBOA) have rarely been documented. OBJECTIVES: To report concomitant sensitizations in patients with allergic contact dermatitis (ACD) from the glucose sensor FreeStyle Libre and sensitized to IBOA. METHODS: In 2019, 26 patients with suspected ACD from FreeStyle Libre were patch tested to a baseline series and to a (meth) acrylate series containing IBOA and 2-phenoxyethyl acrylate (PEA) 0.1% pet. Diabetes devices and patch test preparations were analyzed with gas chromatography - mass spectrometry (GC-MS) for the presence of IBOA and PEA. RESULTS: Of the 26 patients, 18 (69%) were sensitized to IBOA, and eight (44%) and 11 (61%) of these were co-sensitized to sesquiterpene lactones and fragrances, respectively. Ten patients (56%) were co-sensitized to PEA, which, contrary to IBOA, could not be detected in any device. The PEA test material was shown to be contaminated with IBOA. CONCLUSIONS: Contact allergy to IBOA appears to be declining and IBOA-sensitized patients are most often co-sensitized to sesquiterpene lactones and fragrances. Vigilance is required when patch testing (acrylate) materials obtained from industry, as these might be contaminated and, hence, alter the results and their interpretation.

The presence of benzophenone in sunscreens and cosmetics containing the organic UV filter octocrylene: A laboratory study.

BACKGROUND: The reason why patients photosensitized to the drug ketoprofen (KP) may develop severe photoallergic skin reactions to octocrylene (OCT), an organic ultraviolet filter in sunscreens and cosmetics, remains largely unknown. OCT can be synthesized by using unsubstituted benzophenone (BP), a possible human carcinogen. OBJECTIVES: To verify if, and to what extent, BP residues are present in OCT-containing consumer products. METHODS: The raw material of OCT and 39 skincare products, of which 28 contain OCT, were chemically analysed for the presence of BP by means of liquid chromatography. RESULTS: In the OCT raw material and in all 28 OCT-containing products the presence of BP could be demonstrated, mostly in concentrations above 10 ppm (0.001%), whereas a majority of OCT-free products (8/11, 73%) did not contain BP. Moreover, BP concentrations significantly increased, in a time- and temperature-dependent manner, likely due to the additional degradation of OCT. CONCLUSIONS: Photoallergic contact dermatitis from OCT in patients photosensitized to KP might rely on residual BP impurities. Toxicological and ecological studies that evaluate the safety of OCT might also need to consider the concomitant presence of BP.

Characterization of Microbial Degradation Products of Steviol Glycosides.

Steviol glycosides were subjected to bacteria present in a soil sample collected from a Stevia plantation in Paraguay. During the incubation experiments, next to the aglycon steviol, steviol degradation products were also formed. X-ray analysis and NMR methods in combination with chemical synthesis and GIAO NMR calculations were used to fully characterize the structure of these compounds as a tricyclic ketone and the corresponding reduced form. They were nicknamed monicanone and monicanol. The latter has the (S)-configuration at the alcohol site.

Stereoselective Reductions of 3-Substituted Cyclobutanones: A Comparison between Experiment and Theory.

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of cis alcohol (>90%), irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing the solvent polarity. On the computational side, density functional theory and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the antifacial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interactions in the case of a syn-facial hydride attack. The computed cis/trans ratios are in good agreement with the experimental ones and thus show the potential of computational chemistry for predicting and rationalizing the stereoselectivity of hydride reductions of cyclobutanones.

Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative Cross-Coupling of Primary Alcohols.

An intermolecular coupling of primary alcohols and organotriflates has been developed to provide ketones by the action of a Ni(0) catalyst. This oxidative transformation is proposed to occur by the union of three distinct catalytic cycles. Two competitive oxidation processes generate aldehyde in situ via hydrogen transfer oxidation or (pseudo)dehalogenation pathways. As aldehyde forms, a Ni-catalyzed carbonyl-Heck process enables formation of the key carbon-carbon bond. The utility of this rare alcohol to ketone transformation is demonstrated through the synthesis of diverse complex and bioactive molecules.

Introduction of Aryl Fluorosulfates into the Realm of Catellani Reaction Substrates.

Application of activated phenol fluorosulfates as substrates in a Pd/NBE mediated sequential alkylation-arylation, commonly known as a Catellani reaction, is presented. These substrates provide a level of complementarity to the commonly used aryl halides and, in combination with a plethora of existing Catellani reaction variations, enable even wider application of this powerful synthetic tool.

Synthesis of N-Acyl Sulfamates from Fluorosulfates and Amides.

A novel synthetic strategy toward  N-acyl sulfamates was developed. Interestingly, fluorosulfates, a new emerging class of electrophiles, were used to construct the sulfamate core. This precludes handling of chlorosulfonyl isocyanate and sulfamoyl chloride. In combination with amides, a wide and diverse set of N-acyl sulfamates was synthesized, including functionalized bioactive compounds. Furthermore, initial results showed that this method is also amenable to access N-thioacyl sulfamates.

Electrochemistry and Photoredox Catalysis: A Comparative Evaluation in Organic Synthesis.

This review provides an overview of synthetic transformations that have been performed by both electro- and photoredox catalysis. Both toolboxes are evaluated and compared in their ability to enable said transformations. Analogies and distinctions are formulated to obtain a better understanding in both research areas. This knowledge can be used to conceptualize new methodological strategies for either of both approaches starting from the other. It was attempted to extract key components that can be used as guidelines to refine, complement and innovate these two disciplines of organic synthesis.

Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl Bromides or Fluorosulfates: Palladium-Catalyzed Carbonylation.

A palladium-catalyzed carbonylative approach for the direct conversion of (hetero)aryl bromides into their α,α-bis(trifluoromethyl)carbinols is described, and it employs only stoichiometric amounts of carbon monoxide and trifluoromethyltrimethylsilane. In addition, aryl fluorosulfates proved highly compatible with these reaction conditions. The method is tolerant of a diverse set of functional groups, and it is adaptable to late-stage carbon-isotope labeling.

Carbonylation as a novel method for the assembly of pyrazine based oligoamide alpha-helix mimetics.

The design and synthesis of oligoamide α-helix peptidomimetics is reported. The oligoamide type systems are prepared in a modular fashion by coupling the monomers using palladium-catalyzed carbonylation chemistry. This enabled us to use substrates with a low nucleophilicity, leading to previously unreported pyrazine based oligoamide α-helix mimetics. The proof of principle is given by synthesizing a small set of compounds. Various end-capping groups were introduced and also a mixed multimer was successfully prepared.