A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids.

We report an iron-catalyzed decarboxylative C(sp3)-O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV-Vis, HRMS and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C-C and C-heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents.

Exploring the Influence of the Phosphorus-Heteroatom Substitution in Nicotine on Its Electronic and Vibrational Spectroscopic Properties.

The influence of phosphorus substitution of nitrogen in heterocyclic compounds on the vibrational spectroscopy as well as frontier molecular orbitals are analyzed. Nicotine with two nitrogen atoms in its structure is taken as the sample system to be studied computationally. By replacing the nitrogen atom in one or both rings of this molecule with phosphorus, three nicotine derivatives are created. The vibrational circular dichroism and infrared spectra of these four molecules in their monomer state, as well as the assemblies up to trimers are determined. The aforementioned spectra are calculated using static quantum chemical calculations employing a cluster-weighted approach. The calculated gas phase spectra of nicotine are compared to their respective experimental spectra. It is observed that the nicotine derivatives with phosphorus in the methylpyrrolidine ring have considerably different gas phase and bulk phase vibrational circular dichroism spectra when compared to nicotine. The phosphorus substitution reduces the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital as well as altering the polarizability and reactivity of the investigated molecules.

Thermodynamics of Tri- and Tetraepoxyimidazolium NTf2 Amine Polyaddition: A Theoretical Perspective.

The thermodynamics of newly designed tri- and tetraepoxyimidazolium NTf2 monomers reacting with several diamines used as curing agents to form epoxy/amine thermosets was studied. The ability of each epoxy/amine combination to induce cross-linking both through the substitution of multiple epoxy groups and through multiple additions to a single amine was investigated. Through an increased understanding of the thermodynamics of epoxy-amine polymerization in complex polyepoxy-ILs, it is possible to more thoroughly understand the factors affecting the reactivity in these complex systems. These calculations showed that while each possible epoxy-amine combination was exergonic to both forms of cross-linking, the degree to which both amines-induced cross-linking and epoxy-induced cross-linking was favored varied between epoxy-amine combinations. Thermodynamic results obtained using density functional theory were experimentally validated through differential scanning calorimetry results, wherein similar trends were noted between theory and experiment. Among the trends noted in amines-epoxy combinations tested, tetraepoxyimidazolium NTf2/PACM (i.e., a cycloaliphatic diamine) was found to be a prime candidate for amine cross-linking, with the addition of a second epoxy to a single amine group being notably the most negative of all epoxy-amine combinations at -77.6 kJ mol-1. While in the case of epoxy cross-linking, the aliphatic polyetheramine denoted Jeffamine-D230-containing systems were found to be the most exergonic, with additions of primary amines to triepoxyimidazolium and tetraepoxyimidazolium NTf2 averaging -86.9 kJ mol-1. Interaction energy analysis indicated that the aromatic amine named sulfanilamide is the most favorable to engage in reactions due to having the most negative interaction energies with already highly substituted epoxy monomers. These results can be used to adjust the cross-linking possibilities of tri- and tetraepoxyimidazolium NTf2/amine polymerization and give insight into the predominant cross-linking reactions in these unique systems.

Locality in amino-acid based imidazolium ionic liquids.

Several amino-acid based imidazolium ILs are investigated through the use of ab initio molecular dynamics (AIMD), which includes full polarization. The electric dipole moment distribution and polarization is used as a means of characterizing and understanding these complex systems. Various charge scheme methods were analyzed (Wannier function, Blöchl, Löwdin and Mulliken charge schemes and Voronoi tessellation) to determine their ability to predict dipole moments. These results and the following comparison of methods further deepen the knowledge of polarization by highlighting the importance of the anion and cation separately on polarizability contribution and the need to select a suitable method to predict these. The angular probability distribution is utilized to measure the degree of locality in monopole-dipole electrostatic interactions, which showed no preferential alignment over 700 pm. In addition, the IR and Raman spectra from Voronoi tessellation of [C2C1Im][ala] were analyzed. In these, the strongest signalling peaks showed consistency with experiment and the ability to differentiate between anion and cation components of the IL.

Solvent Dependency of Catalyst-Substrate Aggregation Through π-π Stacking in Photoredox Catalysis.

Assemblies of photoredox catalysts and their target substrates prior to photoexcitation is a phenomenon naïvely overlooked by the majority of synthetic chemists, but can have profound influences on reactivity and selectivity in photocatalytic reactions. In this study, we determine the aggregation states of triarylamine radical cationic photocatalysts with various target arene substrates in different solvents by specifically parameterized polarizable molecular dynamics simulations. A π-stacking interaction previously implicated by more expensive, less-representative quantum calculations is confirmed. Critically, this study presents new insights on: i) the ability of solvents (MeCN vs DMF) to make or break a photocatalytic reaction by promoting (MeCN) or demoting (DMF) its catalyst-substrate assemblies, which is a determining factor for reactivity, ii) the average "lifetimes" of assemblies in solution from a dynamic simulation. We find that both in the ground state and the photoexcited state, the cationic radical assemblies remain intact for periods often higher than 60 ps, rendering them ideally suitable to undergo intra-assembly electron transfer reactions upon photoexcitation. Such aspects have not addressed by previous studies on synthetic photocatalytic reactions involving non-covalent assemblies.

On the Rich Chemistry of Pseudo-Protic Ionic Liquid Electrolytes.

Mixing weak acids and bases can produce highly complicated binary mixtures, called pseudo-protic ionic liquids, in which a complex network of effects determines the physicochemical properties that are currently impossible to predict. In this joint computational-experimental study, we investigated 1-methylimidazole-acetic acid mixtures through the whole concentration range. Effects of the varying ionization and excess of either components on the properties, such as density, diffusion coefficients, and overall hydrogen bonding structure were uncovered. A special emphasis was put on understanding the multiple factors that govern the conductivity of the system. In the presence of an excess of acetic acid, the 1-methylimidazolium acetate ion pairs dissociate more efficiently, resulting in a higher concentration of independently moving, conducting ions. However, the conductivity measurements showed that higher concentrations of acetic acid improve the conductivity beyond this effect, suggesting in addition to standard dilution effects the occurrence of Grotthuss diffusion in high acid-to-base ratios. The results here will potentially help designing novel electrolytes and proton conducting systems, which can be exploited in a variety of applications.

Theoretical Analysis of Physical and Chemical CO2 Absorption by Tri- and Tetraepoxidized Imidazolium Ionic Liquids.

The efficient capture of CO2 from flue gas or directly from the atmosphere is a key subject to mitigate global warming, with several chemical and physical absorption methods previously reported. Through polarizable molecular dynamics (MD) simulations and high-level quantum chemical (QC) calculations, the physical and chemical absorption of CO2 by ionic liquids based on imidazolium cations bearing oxirane groups was investigated. The ability of the imidazolium group to absorb CO2 was found to be prevalent in both the tri- and tetraepoxidized imidazolium ionic liquids (ILs) with coordination numbers over 2 for CO2 within the first solvation shell in both systems. Thermodynamic analysis of the addition of CO2 to convert epoxy groups to cyclic carbonates also indicated that the overall reaction is exergonic for all systems tested, allowing for chemical absorption of CO2 to also be favored. The rate-determining step of the chemical absorption involved the initial opening of the epoxy ring through addition of the chloride anion and was seen to vary greatly between the epoxy groups tested. Among the groups tested, the less sterically hindered monoepoxy side of the triepoxidized imidazolium was shown to be uniquely capable of undergoing intramolecular hydrogen bonding and thus lowering the barrier required for the intermediate structure to form during the reaction. Overall, this theoretical investigation highlights the potential for epoxidized imidazolium chloride ionic liquids for simultaneous chemical and physical absorption of CO2.

Mind the target: programmed death ligand 1 in oesophagogastric cancers.

PURPOSE OF REVIEW: Metastatic oesophagogastric cancers carry a prognosis of generally less than 2 years despite current treatment. There has been recent excitement in the field focused on immune checkpoint inhibition though anti-PD-1 antibodies. In this article, we review recent phase 3 clinical trials evaluating first line PD-L1 inhibition in metastatic HER-2-negative oesophagogastric cancers and discuss future questions and challenges in the field. RECENT FINDINGS: Prior studies have shown promise using PD-L1 inhibition as third and fourth line treatment but recent phase 3 clinical trials have shown clear benefit to overall survival as first line treatment. PD-L1 inhibition as monotherapy demonstrated earlier death rates but there are a subset of patients with a long-term durable benefit when compared with chemotherapy. PD-L1 inhibition when combined with chemotherapy showed benefit in overall survival and progression-free survival and is enhanced in subsets of patients with increased PD-L1 expression. SUMMARY: Although there are still open questions how best to assess PD-L1 status, these studies provide clear evidence for use of PD-L1 inhibition combined with cytotoxic chemotherapy as first-line treatment in metastatic or unresectable oesophagogastric cancers that express PD-L1. In addition, they lay the groundwork for future studies evaluating PD-1 inhibition in earlier stages of disease.

Electrochemical characterization and thermodynamic analysis of TEMPO derivatives in ionic liquids.

In this study we investigate the reversibility of the reduction process of three TEMPO derivatives - TEMPOL, 4-cyano-TEMPO, and 4-oxo-TEMPO. The [C2mim][BF4] and [C4mpyr][OTf] ionic liquids (ILs) were used to perform cyclic voltammetry (CV) to analyse the redox potentials of the TEMPO derivatives. The former was previously shown to quench the aminoxy anion of TEMPO through a proton transfer reaction with the cation, whereas the latter supported the irreversibility of the TEMPO reduction process. In CV results on TEMPO derivatives, it was shown that [C4mpyr][OTf] could allow for a high degree of reversibility in the reduction of 4-cyano-TEMPO and a moderate degree of reversibility in the reduction of TEMPOL. In comparison, reduction of 4-cyano-TEMPO was predominantly irreversible in [C2mim][BF4], whilst TEMPOL showed complete irreversibility. 4-Oxo-TEMPO did not show any notable reduction reversibility in either IL tested. Reduction potentials showed little variation between the derivatives and 0.2 V variation between the ILs, with the most negative reduction potential being observed at -1.43 V vs. Fc/Fc+ for TEMPOL in [C4mpyr][OTf]. To explain the varying degrees of reversibility of the reduction process, four types of side reactions involving proton transfer to the aminoxy anion were studied using highly correlated quantum chemical methods. Proton transfer from the IL cation was shown to have the ability to quench all three aminoxy anions depending on the IL used. On average, TEMPOL was shown to be the most susceptible to proton transfer from the IL cation, having an average Gibbs free energy (GFE) of 10.5 kJ mol-1 more negative than that of 4-cyano-TEMPO, which was shown to have the highest GFE of proton transfer. Side reactions between water and aminoxy anions were also seen to have the potential to contribute to degradation of the aminoxy anions tested, with 4-oxo-TEMPO being shown to be the most reactive to degradation with water with a GFE of -12.6 kJ mol-1. 4-Oxo-TEMPO was found to be highly susceptible to self-quenching by its aminoxy anion and radical form with highly negative proton transfer GFEs of -47.9 kJ mol-1 and -57.7 kJ mol-1, respectively. Overall, 4-cyano-TEMPO is recommended as being the most stable of the aminoxy anions tested with TEMPOL, thus providing a viable alternative to improve solubility should the IL be tuned to maximize its stability.

Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma.

Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene program driving mitotic exit and neuronal differentiation. IMPLICATIONS: These findings indicate that targeting phosphorylation of ASCL1 may offer a new approach to development of differentiation therapies in neuroblastoma. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/12/1759/F1.large.jpg.

Isomers of Alkali Metal (Methylbenzyl)allylamides: A Theoretical Perspective.

Recent studies of alkali metal N-(α-methylbenzyl)allylamides containing lithium, sodium, and potassium have shown unique rearrangements in NMR experiments. It was found that lithium isomers favored the formation of aza-allyl and aza-enolate complexes that could exist in a solution for a substantial amount of time. As the radius of the metal ion increases going from lithium to potassium, so does the preference for the formation of the imine structure. For sodium, the aza-allyl complex could still be isolated, whereas the imine structure was only found to be stable on the scale of several hours for potassium. In this work, ab initio calculations were used to shed light on this phenomenon. Decomposition of intermolecular interaction energies of the aza-allyl, aza-enolate, and imine complexes showed that for lithium, the formation of aza-allyl and aza-enolate complexes was driven by electrostatic interactions. For potassium, the dispersion component of the metal interaction with the ligand proved to be more important for the stability of the imine structure. The presence of the imine formation in potassium and partially in sodium was found to be due to the reduced electrostatic nature of these larger metals. The assignment of the experimental NMR spectra was further confirmed with the natural bond order (NBO) analysis as well as the partial charge calculations. Analysis of orbital energies, specifically those of the highest occupied molecular orbitals (HOMOs), as well as the deformation energies of each of the ligands, were also considered. Through these procedures, an understanding of the tendency for each metal to have a unique isomerization pathway was gained.

Somatic mutations and clonal dynamics in healthy and cirrhotic human liver.

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

Increased stability of nitroxide radicals in ionic liquids: more than a viscosity effect.

Radical stability has been subject to continuous research due to its importance in polymerization as well as in all-organic batteries. Recently, the SOMO-HOMO conversion was identified as the main factor in controlling the stability of distonic radicals, for which the negative charge resides on the same molecule. Based on this finding, the idea of ionic liquids stabilizing radicals was hypothesized in this study. A series of ionic liquids were tested in EPR measurements of the 3-carboxy-2,2,5,5-tetramethyl-pyrroline-1-oxyl. Unusually high rotational diffusion constants (τR), 4 times larger compared to conventional media such as dichloromethane (DCM), were recorded at room temperature. This finding could only be explained by a strong interaction existing between the radical and ionic liquid ions, which was confirmed with quantum chemical calculations, with interaction energies falling between -17.1 kJ mol-1 for tetramethylphosphonium tetrafluoroborate and -85.6 kJ mol-1 for 1,3-dimethylimidazolium triflate. Elevated temperature measurements performed at 80 °C reduced the viscosity of the ionic liquids to that of DCM, while the τR values remained relatively high, thus further confirming that the rotational hindrance occurred due to radical-ionic liquid interactions. The calculated interaction energies between the radical and ionic liquids ions were also found to correlate well with experimental rotational diffusion constants, thus offering us a valuable tool in tailoring ionic liquids for enhanced stability of nitroxide radicals. The findings of this study showcase the ability of ionic liquids to reduce reactivity of nitroxides without the need for any chemical modification of the radical.

Is it possible to control kinetic rates of radical polymerisation in ionic liquids?

Experimental studies have noted the often surprising and unpredictable effect of ionic liquids as solvents on reaction kinetics for radical polymerisation. We theoretically investigate the energetic and structural effects of ionic liquids, both protic and aprotic, on radical stability, presenting stabilisation of the radical by the ionic liquid by up to -78.0 kJ mol-1. Kinetic data relating to propagating systems for several industrially viable monomers indicate that propagation rates can be increased or decreased (by up to 6 orders of magnitude) depending on the monomer and ionic liquid combination. The interplay of activation entropy and activation enthalpy, much of which depends on hydrogen bonding between the solvent and reactants, play a crucial role in controlling reaction kinetics. It is concluded that the use of cheaper protic ionic liquids as solvents may be viable for improved kinetic control over radical reactions.

Application of spin-ratio scaled MP2 for the prediction of intermolecular interactions in chemical systems.

Accurate prediction of intermolecular interactions plays a pivotal role in many areas of chemistry and biology including (but not limited to) the design of pharmaceuticals, solid electrolytes and food additives. Here we present the application of the recently developed spin-ratio scaled MP2 method (termed SRS-MP2) to six different datasets covering a wide range of interaction types from strong hydrogen bonding to van der Waals dispersion and π-π stacking. The method achieves a remarkably low mean absolute error of 1.6 kJ mol-1 across all interaction types including semi-Coulombic systems such as organic ionic salts. The new SRS-MP2 method offers high level of accuracy for studying intermolecular interactions commonly found in molecular systems of chemical and biological relevance without the need for including additional terms in the formulation. This finding represents a new paradigm in the development of wavefunction-based methods for intermolecular interactions.

Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma.

Neuroblastoma (NB), although rare, accounts for 15% of all paediatric cancer mortality. Unusual among cancers, NBs lack a consistent set of gene mutations and, excluding large-scale chromosomal rearrangements, the genome seems to be largely intact. Indeed, many interesting features of NB suggest that it has little in common with adult solid tumours but instead has characteristics of a developmental disorder. NB arises overwhelmingly in infants under 2 years of age during a specific window of development and, histologically, NB bears striking similarity to undifferentiated neuroblasts of the sympathetic nervous system, its likely cells of origin. Hence, NB could be considered a disease of development arising when neuroblasts of the sympathetic nervous system fail to undergo proper differentiation, but instead are maintained precociously as progenitors with the potential for acquiring further mutations eventually resulting in tumour formation. To explore this possibility, we require a robust and flexible developmental model to investigate the differentiation of NB's presumptive cell of origin. Here, we use Xenopus frog embryos to characterise the differentiation of anteroventral noradrenergic (AVNA) cells, cells derived from the neural crest. We find that these cells share many characteristics with their mammalian developmental counterparts, and also with NB cells. We find that the transcriptional regulator Ascl1 is expressed transiently in normal AVNA cell differentiation but its expression is aberrantly maintained in NB cells, where it is largely phosphorylated on multiple sites. We show that Ascl1's ability to induce differentiation of AVNA cells is inhibited by its multi-site phosphorylation at serine-proline motifs, whereas overexpression of cyclin-dependent kinases (CDKs) and MYCN inhibit wild-type Ascl1-driven AVNA differentiation, but not differentiation driven by a phospho-mutant form of Ascl1. This suggests that the maintenance of ASCL1 in its multiply phosphorylated state might prevent terminal differentiation in NB, which could offer new approaches for differentiation therapy in NB.

Neuroblastoma progress on many fronts: the Neuroblastoma Research Symposium.

Neuroblastoma (NBL) is a pediatric tumor of infancy derived from precursor cells of the sympathetic nervous system. Clinicians and researchers in developmental biology and genetics recently met to facilitate meaningful crosstalk and to discuss considerable progress made in the clinical treatment and basic biology of NBL. For instance, discoveries in familial NBL have identified genetic aberrations in Phox2b and Alk that predispose to NBL, while advances in epigenetics and MYCN regulation have also offered insight into NBL pathogenesis and future treatment. Moreover, novel therapeutic avenues are also being explored, including targeted immunotherapies, and innovative radiotherapeutic and chemotherapeutic approaches. This multi-disciplinary meeting was convened to aid the transfer of new biological findings into the clinic and to use clinical advances to inform the basic biological understanding of this devastating disease.