Stimulated Raman scattering (SRS) microscopy in tandem with bioorthogonal Raman labelling strategies is set to revolutionise the direct visualisation of intracellular drug uptake. Rational evaluation ...of a series of Raman-active labels has allowed the identification of highly active labels which have minimal perturbation on the biological efficacy of the parent drug. Drug uptake has been correlated with markers of cellular composition and cell cycle status, and mapped across intracellular structures using dual-colour and multi-modal imaging. The minimal phototoxicity and low photobleaching associated with SRS microscopy has enabled real-time imaging in live cells. These studies demonstrate the potential for SRS microscopy in the drug development process.
Post-translational modifications (PTMs) are used by organisms to control protein structure and function after protein translation, but their study is complicated and their roles are not often well ...understood as PTMs are difficult to introduce onto proteins selectively. Designing reagents that are both good mimics of PTMs, but also only modify select amino acid residues in proteins is challenging. Frequently, both a chemical warhead and linker are used, creating a product that is a misrepresentation of the natural modification. We have previously shown that biotin-chloromethyl-triazole is an effective reagent for cysteine modification to give S-Lys derivatives where the triazole is a good mimic of natural lysine acylation. Here, we demonstrate both how the reactivity of the alkylating reagents can be increased and how the range of triazole PTM mimics can be expanded. These new iodomethyl-triazole reagents are able to modify a cysteine residue on a histone protein with excellent selectivity in 30 min to give PTM mimics of acylated lysine side-chains. Studies on the more complicated, folded protein SCP-2L showed promising reactivity, but also suggested the halomethyl-triazoles are potent alkylators of methionine residues.
Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. ...However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K
CO
, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28-65%).
Stimulated Raman scattering (SRS) microscopy represents a powerful method for imaging label-free drug distribution with high resolution. SRS was applied to image label-free ponatinib with high ...sensitivity and specificity in live human chronic myeloid leukemia (CML) cell lines. This was achieved at biologically relevant, nanomolar concentrations, allowing determination of ponatinib uptake and sequestration into lysosomes during the development of acquired drug resistance and an improved understanding of target engagement.
We report the first total synthesis of samroiyotmycin A (1), a C2‐symmetric 20‐membered anti‐malarial macrodiolide isolated from Streptomyces sp. The convergent synthetic strategy orchestrates ...bisalkyne fragment‐assembly using an unprecedented Schöllkopf‐type condensation on a substituted β‐lactone and an ambitious late‐stage one‐pot alkyne cross metathesis–ring‐closing metathesis (ACM–RCAM) reaction. The demanding alkyne metathesis sequence is achieved using the latest generation of molybdenum alkylidynes endowed with a tripodal silanolate ligand framework. Subsequent conversion to the required E‐alkenes uses contemporary hydrometallation chemistry catalysed by tetrameric cluster {Cp*RuCl}4.
Forging of the 20‐membered macrocylic core of samroiyotmycin A can be readily achieved by combining a Mo‐catalysed one‐pot alkyne cross‐metathesis ring‐closing metathesis of bisalkyne building blocks and Ru‐catalysed hydrometallation chemistry. These key transformations have enabled the first total synthesis of this anti‐malarial C2‐symmetric macrodiolide.
Polymeric nanoparticles (NPs) are attractive candidates for the controlled and targeted delivery of therapeutics in vitro and in vivo. However, detailed understanding of the uptake, location, and ...ultimate cellular fate of the NPs is necessary to satisfy safety concerns, which is difficult because of the nanoscale size of these carriers. In this work, we show how small chemical labels can be appended to poly(lactic acid-co-glycolic acid) (PLGA) to synthesize NPs that can then be imaged by stimulated Raman scattering microscopy, a vibrational imaging technique that can elucidate bond-specific information in biological environments, such as the identification of alkyne signatures in modified PLGA terpolymers. We show that both deuterium and alkyne labeled NPs can be imaged within primary rat microglia, and the alkyne NPs can also be imaged in ex vivo cortical mouse brain tissue. Immunohistochemical analysis confirms that the NPs localize in microglia in the mouse brain tissue, demonstrating that these NPs have the potential to deliver therapeutics selectively to microglia.
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Glioblastoma Multiforme (GBM) is a multifaceted and complex disease, which has experienced no changes in treatment for nearly two decades and has a 5-year survival rate of only 5.4%. ...Alongside challenges in delivering chemotherapeutic agents across the blood brain barrier (BBB) to the tumour, the immune microenvironment is also heavily influenced by tumour signalling. Immunosuppression is a major aspect of GBM; however, evidence remains conflicted as to whether pro-inflammatory or anti-inflammatory therapies are the key to improving GBM treatment. To address both of these issues, particle delivery systems can be designed to overcome BBB transport while delivering a wide variety of immune-stimulatory molecules to investigate their effect on GBM. This review explores literature from the past 3 years that combines particle delivery systems alongside immunotherapy for the effective treatment of GBM.
Formation of a luminescent device by the Huisgen 1,3-dipolar cycloaddition reaction between a Eu(III) complex and dansyl azide is reported. This reaction is catalyzed by a common biological copper(I) ...complex GS-−Cu(I), and the resultant copper(I) catalytic sensor shows a 10-fold enhancement of europium luminescence emission.
A desorption electrospray ionization (DESI) source was built and attached to a Bruker 7T SolariX FT-ICR-MS for the in situ analysis of 14 early synthetic dyestuffs. Optimization using silk and wool ...cloths dyed with rhodamine B concluded that when using a commercial electrospray emitter (part number: 0601815, Bruker Daltonik), a nebulizing gas (N2) pressure of 3.9 bar and a sprayer voltage of 4.5 kV (positive ionization mode) or 4.2 kV (negative ionization mode), a solvent system of 3:1 v/v ACN:H2O, and a sprayer incident angle, α, of 35° gave the highest signal-to-noise ratios on both silk and wool for the samples investigated. The system was applied to modern early synthetic dye references on silk and wool as well as historical samples from the 1893 edition of Adolf Lehne’s Tabellarische Übersicht über die künstliche organischen Farbstoffe und ihre Anwendung in Färberei und Zeugdruck Tabular overview of the synthetic organic dyestuffs and their use in dyeing and printing. The successful analysis of six chemically different dye families in both negative and positive modes showed the presence of known degradation products and byproducts arising from the original synthetic processes in the historical samples. This study demonstrates the applicability and potential of DESI-MS to the field of historical dye analysis.
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