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Over the past years our lab has established a research program towards the late-stage introduction of deuterium into organic molecules using Pd-catalyzed reversible C–H activation as a means to affect hydrogen isotope exchange. Through catalyst design, including the introduction of novel ligand scaffolds, as well as the use of strategically chosen optimization and screening approaches, e.g., exploiting microscopic reversibility by first optimizing de-deuteration processes or using a multi-substrate screening approach, our studies have resulted in a number of synthetically useful labelling protocols and are described herein from a personal perspective. 1 Introduction 2 β-C(sp3)–H Deuteration of Free Carboxylic Acids 3 Nondirected C–H Deuteration of Arenes 4 Nondirected C–H Deuteration of Heteroarenes 5 Conclusion [ABSTRACT FROM AUTHOR]

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug‐discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five‐membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi‐substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand‐based palladium catalysts for nondirected C(sp2)−H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules. [ABSTRACT FROM AUTHOR]

Die Bedeutung deuterierter Verbindungen für eine Vielzahl von Anwendungen, die von mechanistischen Studien bis hin zur Entdeckung von Arzneimitteln reichen, hat erhebliches Interesse an der Entwicklung neuer Methoden für den effizienten Einbau von Deuterium in organische und insbesondere in bioaktive Moleküle geweckt. Fünfgliedrige Heteroaromaten, die im Zentrum dieser Arbeit stehen, sind omnipräsente Motive in bioaktiven Molekülen und die Entwicklung effizienter Methoden zur Deuterierung dieser Verbindungen ist daher ein äußerst wichtiges Ziel der organischen Synthesechemie. Die signifikanten Unterschiede in den chemischen Eigenschaften verschiedener Heteroaromaten erschweren jedoch die Entwicklung allgemein anwendbarer Reaktionsbedingungen, so dass häufig eine separate Optimierungskampagne für jede unterschiedliche Heteroaromatenklasse erforderlich ist. In dieser Studie beschreiben wir die Verwendung eines Multi‐Substrat‐Screening‐Ansatzes, um optimale Reaktionsbedingungen für verschiedene Klassen von Heteroaromaten mit einer minimalen Anzahl von Screening‐Reaktionen zu ermitteln. Mithilfe dieses Ansatzes wurden, aufbauend auf unseren zwei Liganden‐basierten Palladiumkatalysatoren für die nicht‐dirigierte C(sp2)−H Aktivierung von Aromaten, vier komplementärere Reaktionsbedingungen identifiziert, die zusammen die Deuterierung strukturell vielseitiger Heteroaromaten, einschließlich bioaktiver Moleküle, ermöglichen. [ABSTRACT FROM AUTHOR]

This article provides a novel approach to assess the importance of specific treatment phases within a treatment regimen through tipping point analyses (TPA) of a time-to-event endpoint using rank-preserving-structural-failure-time (RPSFT) modeling. In oncology clinical research, an experimental treatment is often added to the standard of care therapy in multiple treatment phases to improve patient outcomes. When the resulting new regimen provides a meaningful benefit over standard of care, gaining insights into the contribution of each treatment phase becomes important to properly guide clinical practice. New statistical approaches are needed since traditional methods are inadequate in answering such questions. RPSFT modeling is an approach for causal inference, typically used to adjust for treatment switching in randomized clinical trials with time-to-event endpoints. A tipping-point analysis is commonly used in situations where a statistically significant treatment effect is suspected to be an artifact of missing or unobserved data rather than a real treatment difference. The methodology proposed in this article is an amalgamation of these two ideas to investigate the contribution of a specific component of a regimen comprising multiple treatment phases. We provide different variants of the method and construct indices of contribution of a treatment phase to the overall benefit of a regimen that facilitates interpretation of results. The proposed approaches are illustrated with findings from a recently concluded, real-life phase 3 cancer clinical trial. We conclude with several considerations and recommendations for practical implementation of this new methodology. [ABSTRACT FROM AUTHOR]

Two new zinc(II) complexes, [2,6‐bis(methylphenyliminomethyl)pyridine]ZnBr2 (2 a) and [2,6‐bis(triflouromethylphenyliminomethyl)pyridine]ZnBr2 (2 b) were synthesized by the reactions of corresponding 2,6‐bis(imino)pyridine based [NNN]‐pincer ligand and anhydrous ZnBr2 in acetonitrile as a solvent. The catalytic properties of zinc(II) complexes were examined in azide‐alkyne cycloaddition reactions in water. The zinc(II) complexes were characterized by UV‐Vis, 1H NMR, IR, elemental analysis and mass spectroscopy. The zinc complex [2,6‐bis(triflouromethylphenyliminomethyl)pyridine]ZnBr2 was characterized by X‐ray crystallography. The zinc(II) complexes efficiently catalyzed the azide‐alkyne cycloaddition reaction for the synthesis of 1,2,3‐triazoles (mixture of 1,4‐ and 1,5‐disubstituted 1,2,3‐triazoles) in water with good to excellent yields. [ABSTRACT FROM AUTHOR]

We report the results obtained from a multiwavelength study of the H ii region G18.148âˆ'0.283 using the upgraded Giant Metrewave Radio Telescope at 1350 MHz, along with other archival data. In addition to the radio continuum emission, we have detected the H169 α and H170 α radio recombination lines toward G18.148âˆ'0.283 using a correlator bandwidth of 100 MHz. The moment-1 map of the ionized gas reveals a velocity gradient of approximately 10 km sâˆ'1 across the radio continuum peaks. The 12CO (J = 3âˆ'2) molecular line data from the CO High-Resolution Survey (COHRS) also show the presence of two velocity components that are very close to the velocities detected in the ionized gas. The spectrum and positionâ€"velocity diagram from CO emission reveal molecular gas at an intermediate-velocity range bridging the velocity components. We see mid-infrared absorption and far-infrared emission establishing the presence of a filamentary infrared dark cloud, the extent of which includes the targeted H ii region. The magnetic field inferred from dust polarization is perpendicular to the filament within the H ii region. We have also identified two O9 stars and 30 young stellar objects toward the target using data from the Two Micron All Sky Survey (2MASS), UKIRT Infrared Deep Sky Survey (UKIDSS), and Galactic Legacy Infrared Midplane Survey Extraordinaire (GLIMPSE). Cumulatively, this suggests that the region is the site of a cloudâ€"cloud collision that has triggered massive star formation and subsequent formation of an H ii region. [ABSTRACT FROM AUTHOR]

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention‐to‐treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment‐policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross‐industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

Synthesis and stabilization of ultra-small metal nanoparticles (MNPs) composed of a few atoms are of paramount importance in modulating their material properties based on quantum confinement effects. The highly reactive surface of small MNPs tends to aggregate, resulting in bigger particles and subsequent deterioration of the catalytic activity. In this work, we exploited a dithienylethene (DTE) based photochromic organic cage (TAE-DTE) for the in situ stabilization of ultra-small Au NPs (Au@TAE-DTE) (<2 nm) through a unique "reverse double-solvent approach (RDSA)". The Au@TAE-DTE showed similar photochromic properties to the TAE-DTE and shuttled between two metastable photoisomers, Au@TAE-DTE-O and Au@TAE-DTE-C, based on DTE ring opening and closing upon treating with visible and UV-light, respectively. The Au@TAE-DTE hybrid showed visible light (λ = 400–750 nm) driven catalytic activity for photochemical CO2 reduction to CO. Importantly, irradiating with light of the full range (λ = 250–750 nm) allowed for co-existence of both photoisomers which thereby showed wide spectrum absorption as compared to individual photoisomers, consequently displaying substantially enhanced performance for the photocatalytic CO2 reduction. Further, the real-time progress of the CO2 reduction reaction and corresponding reaction intermediates was detected by an in situ DRIFT experiment. [ABSTRACT FROM AUTHOR]

The study of the intensity fluctuation power spectrum of individual supernova remnants (SNRs) can reveal the structures present at sub-pc scales, and also constrain the physical process that generates those structures. There are various effects, such as the remnant shell thickness, projection of a three-dimensional structure on to a two-dimensional observational plane, and the presence of diffuse 'foreground' emission, which causes the observed power spectrum to deviate from the intrinsic power spectrum of the fluctuations. Here, we report results from a systematic study of these effects, using direct numerical simulations, in the measured power spectrum. For an input power-law power spectrum, independent of the power-law index, we see a break in the observed power law at a scale which depends on the shell thickness of a shell-type SNR, and the three-dimensional turbulence changes to two-dimensional turbulence beyond that scale. We also report how the estimated power spectrum is expected to deviate from the intrinsic SNR power spectrum in the presence of additional diffuse Galactic synchrotron emission (DGSE) around the remnant shell. For a reasonable choice of the parameters, if the intrinsic SNR power spectrum is shallower than the DGSE power spectrum, the SNR contribution dominates at small angular scales of the estimated power spectra. On the other hand, if the SNR power spectrum is relatively steeper, the original power spectra is recovered only over a small window of angular scales. This study shows how detailed modelling may be used to infer the true power spectrum from the observed SNR intensity fluctuations power spectrum, which in turn can be used to constrain the nature of the turbulence that gives rise to these small-scale structures. [ABSTRACT FROM AUTHOR]