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Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

The magic methyl effect is well acknowledged in medicinal chemistry, but despite its significance, accessing such analogues via derivatization at a late stage remains a pivotal challenge. In an effort to mitigate this major limitation, we here present a strategy for the cobalt-catalysed late-stage C–H methylation of structurally complex drug molecules. Enabling broad applicability, the transformation relies on a boron-based methyl source and takes advantage of inherently present functional groups to guide the C–H activation. The relative reactivity observed for distinct classes of functionalities were determined and the sensitivity of the transformation towards a panel of common functional motifs was tested under various reaction conditions. Without the need for prefunctionalization or postdeprotection, a diverse array of marketed drug molecules and natural products could be methylated in a predictable manner. Subsequent physicochemical and biological testing confirmed the magnitude with which this seemingly minor structural change can affect important drug properties.Despite the importance of C–H methylation in medicinal chemistry, the application to densely functionalized complex molecules remains a challenge. Now, a novel cobalt-catalysed method takes advantage of inherently present functional groups to guide the C–H activation and a boron-based methyl source enables the late stage C–H methylation of pharmaceutically relevant substrates.

Catalysed C–H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp 3 -rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta -C( sp 2 )–H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C–H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes. Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta -C–H alkylation method facilitating the biological properties modulation of therapeutic agents.

The main function of translation initiation factors is to assist ribosomes in selecting the correct reading frame on an mRNA. This process has been extensively studied with the help of reconstituted in vitro systems, but the dynamics in living cells have not been characterized. In this study, we performed single-molecule tracking of the bacterial initiation factors IF2, IF3, as well as the initiator fMet-tRNA fMet directly in growing Escherichia coli cells. Our results reveal the kinetics of factor association with the ribosome and, among other things, highlight the respective antagonistic roles of IF2 and IF3 in the process. Importantly, our comparisons of in vivo binding kinetics of two naturally occurring isoforms of IF2 reveal that the longer IF2α isoform directly interacts with the transcriptional factor NusA, a finding further corroborated by pull-down and cross-linking experiments. Our results suggest that this interaction may promote formation of a coupled transcription-translation complex early in the translation cycle, motivating further structural studies to validate the mechanism. We further show that cells with compromised binding between IF2α and NusA display slow adaptation to new growth conditions. The in vivo dynamics of bacterial translation initiation has remained unexplored. Here, the authors measured ribosome binding kinetics of the key factors directly inside living E. coli cells, using single-molecule tracking techniques, and found novel link between translation and transcription.

Transition metal-catalysed C–H activation has emerged as an increasingly powerful platform for molecular syntheses, enabling applications to natural product syntheses, late-stage modification, pharmaceutical industries and material sciences, among others. This Primer summarizes representative best practices for the experimental set-up and data deposition for C–H activation, as well as discussing key developments including recent advances in asymmetric, photoinduced and electrocatalytic C–H activation. Likewise, strategies for applications of C–H activation towards the assembly of structurally complex (bio)polymers and drugs in academia and industry are discussed. In addition, current limitations in C–H activation and possible approaches for overcoming these shortcomings are reviewed.This Primer provides an overview of the best practices for C–H activation as well as key advances in asymmetric, photoinduced and electrocatalytic-mediated catalysis for this synthetic platform. An overview of how C–H activation facilitates the synthesis of molecules such as structurally complex (bio)polymers and drugs is provided along with the current challenges and priorities for the next decade.

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C–H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools. PROTACs are uniquely powerful therapeutic agents, but their synthetic tractability significantly limit drug discovery programs. Here, the authors developed a single step synthesis of PROTAC conjugates via late stage ruthenium-catalysed C–H amidation.

Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C−H activations, these arene functionalizations generally require directing groups to enable the C−H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C−H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C−H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C−H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C−H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations. Electrochemistry has emerged as an increasingly viable tool in molecular synthesis. Here the authors realize electrocatalyzed C−H activations, with the aid of data science and artificial intelligence, towards selective alkenylations for late-stage drug diversifications.

Background This paper describes the development and psychometric evaluation of a behavioral assessment instrument primarily intended for use with workgroups in any type of organization. The instrument was developed based on the Nurturing Environments framework which describes four domains important for health, well-being, and productivity; minimizing toxic social interactions, teaching and reinforcing prosocial behaviors, limiting opportunities for problem behaviors, and promoting psychological flexibility. The instrument is freely available to use and adapt under a CC-BY license and intended as a tool that is easy for any group to use and interpret to identify key behaviors to improve their psychosocial work environment. Methods Questionnaire data of perceived frequency of behaviors relevant to nurturance were collected from nine different organizations in Sweden. Data were analyzed using confirmatory factor analysis, Rasch analysis, and correlations to investigate relationships with relevant workplace measures. Results The results indicate that the 23-item instrument is usefully divided in two factors, which can be described as risk and protective factors. Toxic social behaviors make up the risk factor, while the protective factor includes prosocial behavior, behaviors that limit problems, and psychological flexibility. Rasch analysis showed that the response categories work as intended for all items, item fit is satisfactory, and there was no significant differential item functioning across age or gender. Targeting indicates that measurement precision is skewed towards lower levels of both factors, while item thresholds are distributed over the range of participant abilities, particularly for the protective factor. A Rasch score table is available for ordinal to interval data transformation. Conclusions This initial analysis shows promising results, while more data is needed to investigate group-level measurement properties and validation against concrete longitudinal outcomes. We provide recommendations for how to work in practice with a group based on their assessment data, and how to optimize the measurement precision further. By using a two-dimensional assessment with ratings of both frequency and perceived importance of behaviors the instrument can help facilitate a participatory group development process. The Group Nurturance Inventory is freely available to use and adapt for both commercial and non-commercial use and could help promote transparent assessment practices in organizational and group development.

Secondary amines are vital functional groups in pharmaceuticals, agrochemicals, and natural products, necessitating efficient synthetic methods. Traditional approaches, including N -monoalkylation and reductive amination, suffer from limitations such as poor chemoselectivity and complexity. Herein, we present a streamlined deoxygenative photochemical alkylation of secondary amides, enabling the efficient synthesis of α-branched secondary amines. Our method leverages triflic anhydride-mediated semi-reduction of amides to imines, followed by a photochemical radical alkylation step. This approach broadens the synthetic utility of amides, facilitating late-stage modifications of drug-like molecules and the synthesis of saturated N -substituted heterocycles. The pivotal role of flow technology in developing a scalable and robust process underscores the practicality of this method, significantly expanding the organic chemist’s toolbox for complex amine synthesis. Traditional approaches for the synthesis of secondary amines suffer from limitations such as poor chemoselectivity and lack of versatility. Herein, the authors present a streamlined deoxygenative photochemical alkylation of secondary amides, enabling the synthesis of α-branched secondary amines.

Reaching sub-millisecond 3D tracking of individual molecules in living cells would enable direct measurements of diffusion-limited macromolecular interactions under physiological conditions. Here, we present a 3D tracking principle that approaches the relevant regime. The method is based on the true excitation point spread function and cross-entropy minimization for position localization of moving fluorescent reporters. Tests on beads moving on a stage reaches 67 nm lateral and 109 nm axial precision with a time resolution of 0.84 ms at a photon count rate of 60 kHz; the measurements agree with the theoretical and simulated predictions. Our implementation also features a method for microsecond 3D PSF positioning and an estimator for diffusion analysis of tracking data. Finally, we successfully apply these methods to track the Trigger Factor protein in living bacterial cells. Overall, our results show that while it is possible to reach sub-millisecond live-cell single-molecule tracking, it is still hard to resolve state transitions based on diffusivity at this time scale. Single-molecule 3D tracking is critical to understand macromolecular dynamics but achieving this at a sub-millisecond resolution remains challenging. Here the authors present a 3D tracking method based on cross-entropy minimization and the true excitation point spread function.