Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics.

Objective: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs).

Methods: We developed C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs).

Sulfonated Hydroxyaryl-Tetrazines with Increased pK for Accelerated Bioorthogonal Click-to-Release Reactions in Cells.

Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine-mediated cleavage of trans-cyclooctene caged compounds (click-to-release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans-cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo-tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (pK).

Transforming Aryl-Tetrazines into Bioorthogonal Scissors for Systematic Cleavage of trans-Cyclooctenes.

Bioorthogonal bond-cleavage reactions have emerged as a powerful tool for precise spatiotemporal control of (bio)molecular function in the biological context. Among these chemistries, the tetrazine-triggered elimination of cleavable trans-cyclooctenes (click-to-release) stands out due to high reaction rates, versatility, and selectivity. Despite an increasing understanding of the underlying mechanisms, application of this reaction remains limited by the cumulative performance trade-offs (i.

Bioorthogonal Chemistry in Cellular Organelles.

While bioorthogonal reactions are routinely employed in living cells and organisms, their application within individual organelles remains limited. In this review, we highlight diverse examples of bioorthogonal reactions used to investigate the roles of biomolecules and biological processes as well as advanced imaging techniques within cellular organelles. These innovations hold great promise for therapeutic interventions in personalized medicine and precision therapies.

Facile Approach to C-Glucosides by Using a Protecting-Group-Free Hiyama Cross-Coupling Reaction: High-Yielding Dapagliflozin Synthesis.

Invited for the cover of this issue is Kamil Parkan and co-workers at University of Chemistry and Technology and Institute of Organic Chemistry and Biochemistry, Prague. The cover graphic depicts a schematic representation of the assembly of aryl-C-glycosides based on a protecting-group-free Hiyama reaction. Read the full text of the article at 10.

Facile Approach to C-Glucosides by Using a Protecting-Group-Free Hiyama Cross-Coupling Reaction: High-Yielding Dapagliflozin Synthesis.

Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding α- and β-C-glucosides, as well as 2-deoxy-β-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus.

Transition-Metal-Mediated versus Tetrazine-Triggered Bioorthogonal Release Reactions: Direct Comparison and Combinations Thereof.

Bioorthogonal cleavage reactions are gaining popularity in chemically inducible prodrug activation and in the control of biomolecular functions. Despite similar applications, these reactions were developed and optimized on different substrates and under different experimental conditions. Reported herein is a side-by-side comparison of palladium-, ruthenium- and tetrazine-triggered release reactions, which aims at comparing the reaction kinetics, efficiency and overall advantages and limitations of the methods.