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.
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.
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
-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp
)-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.
At the early stages of the drug development process, thousands of compounds are synthesized in order to attain the best possible potency and pharmacokinetic properties. Once successful scaffolds are ...identified, large libraries of analogues are made, which is a challenging and time-consuming task. Recently, late stage functionalization (LSF) has become increasingly prominent since these reactions selectively functionalize C–H bonds, allowing to quickly produce analogues. Classical electrophilic aromatic halogenations are a powerful type of reaction in the LSF toolkit. However, the introduction of an electrophile in a regioselective manner on a drug-like molecule is a challenging task. Herein we present a machine learning model able to predict the reactive site of an electrophilic aromatic substitution with an accuracy of 93% (internal validation set). The model takes as input a SMILES of a compound and uses six quantum mechanics descriptors to identify its reactive site(s). On an external validation set, 90% of all molecules were correctly predicted.
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.
Abstract
Introducing amide functional groups under mild conditions has growing importance owing to the prevalence of such moiety in biologically active molecules. Herein, we disclose a mild protocol ...for the directed ruthenium‐catalyzed C−H aminocarbonylation with isocyanates as the amidating agents developed through high‐throughput experimentation (HTE). The redox‐neutral and base‐free reaction is guided by weakly Lewis basic functional groups, including anilides, lactams and carbamates to access anthranilamide derivatives. The synthetic utility of this transformation is reflected by large‐scale synthesis and late‐stage functionalization.
Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits ...available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. The redox‐active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect allowed the asymmetric cyclopropanation of various olefins, including unfunctionalized aliphatic alkenes, that enables the three‐step total synthesis of (−)‐dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally differentiated diazocompounds are viable and advantageous equivalents of single‐carbon chirons.
Going to the source: The asymmetric synthesis of cyclopropanes is currently designed using specific strategies that depend on the materials available and the final functionality of each target. Presented here is a comprehensive approach that engages simple feedstocks, including aliphatic olefins, with a single redox‐active carbene precursor (NHPI‐DA), which acts as a universal source for a chiral C−H unit.
Most countries collect loss and damage data after disasters for learning purposes and in support of future preventive work. The lack of international standards and sharing principles implies ...heterogeneous data sets, thus presenting a challenge to the development of indicators intended to assess progress within the UN agreement Sendai Framework for Disaster Risk Reduction 2015-2030 (SFDRR). In this study, data on mortality, affected people and direct economic losses are extracted from two national databases in Sweden for the years 1996-2015. Pre-SFDRR terminology, definitions and different inclusion criteria are used to exemplify and identify challenges when global "proxy" data inquiry clashes with sub-national demands for data quality. Different test methods on how to estimate affected people are used and in comparison with the term 'directly affected people', as proposed in the SFDRR indicator establishment process, it is concluded that methods for more disaggregated data are needed. In a Swedish context, the SFDRR call for a reference period 2005-2015 is found to be a time too short for providing a fair picture of disaster risks within Sweden's borders. The nationally developed strategy in Sweden, as in many other countries, to learn in-depth after each new disaster and use the experience to remedy weaknesses in safety systems, generates solid data supporting the development of SFDRR indicators, but the national benefits and the relevance of statistics from disasters re-occurring on longer time scales are limited.
Abstract
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
H2O2‐driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source of H2O2 for one of these ...biocatalysts, which is known as unspecific peroxygenase (UPO). OXO is reasonably robust, produces only CO2 as a by‐product and uses oxalate as a cheap sacrificial electron donor. UPO has significant potential as an industrial catalyst for selective C−H oxyfunctionalisations, as we confirm herein by testing a diverse drug panel using miniaturised high‐throughput assays and mass spectrometry. 33 out of 64 drugs were converted in 5 μL‐scale reactions by the UPO with OXO (conversion >70 % for 11 drugs). Furthermore, oxidation of the drug tolmetin was achieved on a 50 mg scale (TONUPO 25 664) with 84 % yield, which was further improved via enzyme immobilization. This one‐pot approach ensures adequate H2O2 levels, enabling rapid access to industrially relevant molecules that are difficult to obtain by other routes.
High‐throughput μL‐scale screenings revealed optimal conditions for in situ H2O2‐generation using oxalate oxidase in bioconversions catalysed by unspecific peroxygenase. This enzymatic tandem exhibits extraordinary potential for selective C−H oxyfunctionalisation reactions of complex drug scaffolds.
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