2D and 3D anticancer properties of C2-functionalised glucosamine-Pt (IV) prodrugs based on cisplatin scaffold.

A series of C2-functionalied Pt (IV) glycoconjugates based on glucosamine have been synthesised, characterised and tested as anticancer agents on a series of different 2D and 3D cancer cell lines. The carbohydrate will act as a targeted delivery system to improve the selectivity, exploiting the Warburg Effect and the GLUTs receptors that are overexpressed in most of the cancer cells. The hydroxyl at C2 of the carbohydrates does not participate in hydrogen bonding with the GLUTs receptors, making C2 an attractive position for drug conjugation as seen in literature. In this study, we use the amino functionality at the C2 position in glucosamine and Copper-catalysed Azide-Alkyne Cycloaddition "click" (CuAAC) reaction to connect the prodrug Pt (IV) scaffold to the carbohydrate. We have investigated complexes with different linker lengths, as well as acetyl protected and free derivatives. To the best of our knowledge, this study represents the first series of Pt (IV) glucosamine-conjugates functionalised at C2.

Development of Novel Pt(IV)-Carbohydrate Derivatives as Targeted Anticancer Agents against Osteosarcoma.

Despite the enormous importance of cisplatin as a chemotherapeutic agent, its application is impacted by dose-limiting side effects and lack of selectivity for cancer cells. Researchers can overcome these issues by taking advantage of the pro-drug nature of the platinum(IV) oxidation state, and by modifying the coordination sphere of the metal centre with specific vectors whose receptors are overexpressed in tumour cell membranes (e.g., carbohydrates). In this paper we report the synthesis of four novel carbohydrate-modified Pt(IV) pro-drugs, based on the cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumour which is most common in adolescents and young adults. The carbohydrate-targeting vectors and Pt scaffold are linked using copper-catalysed azide-alkyne cycloaddition (CuAAC) chemistry, which is synonymous with mild and robust reaction conditions. The novel complexes are characterised using multinuclear 1D-2D NMR (1H, 13C and 195Pt), IR, HR-MS, Elem. Analyses, and CV. Cytotoxicity on 2D and 3D and cell morphology studies on OS cell lines, as well as non-cancerous human foetal osteoblasts (hFOBs), are discussed.

N-Alkyl-2-Quinolonopyrones Demonstrate Antimicrobial Activity against ESKAPE Pathogens Including Staphylococcus aureus.

Antibiotic resistance has grown significantly in the last three decades, while research and development of new antibiotic classes has languished. Therefore, new chemical frameworks for the control of microbial behavior are urgently required. This study presents a novel suite of compounds, based on a tricyclic 4-hydroxy-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione core, with significant antibiotic activity against the ESKAPE pathogens Staphylococcus aureus and Enterococcus faecalis and the "accidental pathogen" Staphylococcus epidermidis. A potent analogue with an N-heptyl-9-t-Bu substitution pattern emerged as a hit with MIC levels ≤2 µg/mL across four strains of MRSA. In addition, the same compound proved highly potent against Enterococcus spp. (0.25 µg/mL).

Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.

There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages.

Quantification of Ion-Implanted Single-Atom Dopants in Monolayer MoS2 via HAADF STEM Using the TEMUL Toolkit.

In recent years, atomic resolution imaging of two-dimensional (2D) materials using scanning transmission electron microscopy (STEM) has become routine. Individual dopant atoms in 2D materials can be located and identified using their contrast in annular dark-field (ADF) STEM. However, in order to understand the effect of these dopant atoms on the host material, there is now the need to locate and quantify them on a larger scale. In this work, we analyze STEM images of MoS2 monolayers that have been ion-implanted with chromium at ultra-low energies. We use functions from the open-source TEMUL Toolkit to create and refine an atomic model of an experimental image based on the positions and intensities of the atomic columns in the image. We then use the refined model to determine the likely composition of each atomic site. Surface contamination stemming from the sample preparation of 2D materials can prevent accurate quantitative identification of individual atoms. We disregard atomic sites from regions of the image with hydrocarbon surface contamination to demonstrate that images acquired using contaminated samples can give significant atom statistics from their clean regions, and can be used to calculate the retention rate of the implanted ions within the host lattice. We find that some of the implanted chromium ions have been successfully integrated into the MoS2 lattice, with 4.1% of molybdenum atoms in the transition metal sublattice replaced with chromium.

TopoTEM: A Python Package for Quantifying and Visualizing Scanning Transmission Electron Microscopy Data of Polar Topologies.

The exotic internal structure of polar topologies in multiferroic materials offers a rich landscape for materials science research. As the spatial scale of these entities is often subatomic in nature, aberration-corrected transmission electron microscopy (TEM) is the ideal characterization technique. Software to quantify and visualize the slight shifts in atomic placement within unit cells is of paramount importance due to the now routine acquisition of images at such resolution. In the previous ~decade since the commercialization of aberration-corrected TEM, many research groups have written their own code to visualize these polar entities. More recently, open-access Python packages have been developed for the purpose of TEM atomic position quantification. Building on these packages, we introduce the TEMUL Toolkit: a Python package for analysis and visualization of atomic resolution images. Here, we focus specifically on the TopoTEM module of the toolkit where we show an easy to follow, streamlined version of calculating the atomic displacements relative to the surrounding lattice and thus plotting polarization. We hope this toolkit will benefit the rapidly expanding field of topology-based nano-electronic and quantum materials research, and we invite the electron microscopy community to contribute to this open-access project.

Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma.

The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are described.

Multiple unbiased approaches identify oxidosqualene cyclase as the molecular target of a promising anti-leishmanial.

Phenotypic screening identified a benzothiophene compound with activity against Leishmania donovani, the causative agent of visceral leishmaniasis. Using multiple orthogonal approaches, oxidosqualene cyclase (OSC), a key enzyme of sterol biosynthesis, was identified as the target of this racemic compound and its enantiomers. Whole genome sequencing and screening of a genome-wide overexpression library confirmed that OSC gene amplification is associated with resistance to compound 1. Introduction of an ectopic copy of the OSC gene into wild-type cells reduced susceptibility to these compounds confirming the role of this enzyme in resistance. Biochemical analyses demonstrated the accumulation of the substrate of OSC and depletion of its product in compound (S)-1-treated-promastigotes and cell-free membrane preparations, respectively. Thermal proteome profiling confirmed that compound (S)-1 binds directly to OSC. Finally, modeling and docking studies identified key interactions between compound (S)-1 and the LdOSC active site. Strategies to improve the potency for this promising anti-leishmanial are proposed.

Plasmons in MoS2 studied via experimental and theoretical correlation of energy loss spectra.

This paper takes a fundamental view of the electron energy loss spectra of monolayer and few layer MoS2 . The dielectric function of monolayer MoS2 is compared to the experimental spectra to give clear criteria for the nature of different signals. Kramers-Krönig analysis allows a direct extraction of the dielectric function from the experimental data. However this analysis is sensitive to slight changes in the normalisation step of the data pretreatment. Density functional theory provides simulations of the dielectric function for comparison and validation of experimental findings. Simulated and experimental spectra are compared to isolate the π and π + σ surface plasmon modes in monolayer MoS2 . Single-particle excitations obscure the plasmons in the monolayer spectrum and momentum resolved measurements give indication of indirect interband transitions that are excited due to the large convergence and collection angles used in the experiment. LAY DESCRIPTION: Two-dimensional materials offer a path forward for smaller and more efficient devices. Their optical and electronic properties give way to beat the limits set in place by Moore's Law. Plasmon are the collective oscillations of electrons and can confine light to dimensions much smaller than its wavelength. In this work we explore the plasmonic properties of MoS2 , a representational candidate from a family of 2D materials known as transition metal dichalcogenides. High resolution electron microscopy and spectroscopy provide insights in the plasmonic properties of MoS2 down to an atomic scale. Experimental results show the relationship between plasmons and interband transitions in the electron energy loss spectrum. Density functional theory provides a theoretical support for the experimental findings and provides commentary on the fundamental underlying physics.