Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Proteostasis is differentially modulated by inhibition of translation initiation or elongation.

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discrete steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis elegans from proteotoxic stress. We systematically challenge proteostasis and show that pharmacologically inhibiting translation initiation or elongation elicits a distinct protective profile. Inhibiting elongation protects from heat and proteasome dysfunction independently from HSF-1 but does not protect from age-associated protein aggregation. Conversely, inhibition of initiation protects from heat and age-associated protein aggregation and increases lifespan, dependent on hsf-1, but does not protect from proteotoxicity caused by proteasome dysfunction. Surprisingly, we find that the ability of the translation initiation machinery to control the concentration of newly synthesized proteins depends on HSF-1. Inhibition of translation initiation in wild-type animals reduces the concentration of newly synthesized proteins but increases it in hsf-1 mutants. Our findings suggest that the HSF-1 pathway is not only a downstream target of translation but also directly cooperates with the translation initiation machinery to control the concentration of newly synthesized proteins to restore proteostasis.

Light Shining within the "Dark" Classics: A Perspective on Entheogenic Compounds.

Several naturally occurring molecules exhibit unique potential in treating certain elements of psychiatric illnesses and are being actively pursued in therapeutic development. Among these are molecules termed entheogens, a preferred name for plant-derived compounds that alter human consciousness for religious or spiritual purposes, which are especially important to various Indigenous groups, and their use within these cultures precedes that of the contemporary medicalized use. Here, we acknowledge that some entheogens were included in the DARK Classics issues of ACS Chemical Neuroscience and that the label of "DARK" may perpetuate harmful and misguided labels and stigmas. We acknowledge that these compounds should really be framed in the light and beauty of their histories and uses culturally. Thus, in this Viewpoint, we consider the language used surrounding entheogens specifically and psychedelics more broadly and attempt to reframe the way we describe psychoactive, especially entheogenic, compounds in ACS Chemical Neuroscience.

Design and Analysis of Pharmacological Studies in Aging.

Measuring lifespan of the model organism, Caenorhabditis elegans, in a 96-well format enables the screening of large chemical libraries to identify biologically active molecules. Furthermore, the wide availability of these animals with specific genetic mutations allows the identification of genes that influence lifespan, and by extension, age-related biological pathways. Here, we present a method for measuring the lifespan of C. elegans in 96-well microtiter plates to identify and study pharmacologically active molecules that extend lifespan. The format of this assay is readily adapted for automated liquid handling systems and imaging of phenotypes.

CITU: A Peptide and Decarboxylative Coupling Reagent.

Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.