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Robinia pseudoacacia (Black Locust) – An Invasive Species with Unsuspected Potential in Grappa Ageing: Highlights of Analytical Sciences in Switzerland
No full textLate-stage Functionalization and its Impact on Modern Drug Discovery: Medicinal Chemistry and Chemical Biology Highlights
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The Role of Transporters in Future Chemotherapy
Get PDFThe expression of membrane transporter is often altered in cancer cells compared to their corresponding healthy cells. Since these proteins, classified into solute carriers (SLCs) and ATP-binding cassettes (ABCs), can carry not only endogenous compounds, nutrients, and metabolites, but also drugs across the cell membranes, they have a crucial role in drug exposure and clinical outcomes of chemotherapeutics. Curiously, up-regulation of SLCs can be exploited to deliver chemotherapeutics, their prodrugs, and diagnostic radio-tracers to gain cancer cell-selective targeting, as exemplified with L-type amino acid transporter 1 (LAT1). SLCs can also be inhibited to limit the nutrient uptake of cancer cells and thus, cell growth and proliferation. Furthermore, LAT1 can be utilized to deliver ABC-inhibitors selectively into the cancer cells to block the efflux of other chemotherapeutics suffering from acquired or intrinsic efflux transport-related multidrug resistance (MDR). Taking into account the current literature, compounds that can affect transporter up- or down-regulation of transporters in a cancer cell-selective manner could be a valuable tool and promising chemotherapy form in the future
Current HDAC Inhibitors in Clinical Trials
Get PDFEpigenetic modifications in eukaryotic biological pathways can lead to the up- or downregulation of regulatory proteins contributing to disease onset and progression. In the last three decades, histone deacetylases (HDACs) are among the most studied epigenetic targets. In fact, aberrant HDAC expression is associated with numerous types of cancer and neurodegenerative disorders, making HDACs promising molecular targets for the design of new drugs. Many HDAC inhibitors (HDACi) are currently in clinical evaluation for various types of cancer, and some of them reached the market after approval by the Food and Drug Administration (FDA). The present review summarizes the various HDAC classes and relative isoforms. Then we discuss different class or isoform-selective HDACi with a strong emphasis on late-stage preclinical candidates and drugs in clinical studies. Last but not least, we shed light on the pharmacokinetic challenges and future directions in HDACi design
The Structural Basis for Metal Ion Transport in the SLC11/NRAMP Family
Get PDFThe SLC11/NRAMP proteins constitute a conserved family of metal ion transporters that are expressed in all kingdoms of life. In humans, the two paralogs DMT1 and NRMP1 play an important role in iron homeostasis and the defense against pathogens. SLC11 transporters have evolved an exquisite selectivity for transition metal ions, which facilitates their efficient transport from a large background of Ca2+ and Mg2+. This is accomplished by the evolution of a conserved binding site, which contains besides promiscuous hard ligands, a methionine acting as soft ligand that exclusively coordinates transition metals and thus contributes to the exclusion of alkaline earth metal ions. This site is altered in a branch of prokaryotic family members, which are capable of transporting Mg2+, where the removal of the coordinating methionine and the accompanying expansion of the binding pocket captures this small ion in a hydrated state. The disposition of titratable residues in H+-coupled transition metal ion transporters, that are absent in uncoupled Mg2+ transporters, sheds light on potential coupling mechanisms. In combination, the discussed work has revealed detailed insight into transition metal ion transport and provides a basis for the development of inhibitors of DMT1 as strategy against iron overload disorders
Monitoring of On-Site generated Hypochlorite for Water Disinfection: FH-HES Universities of Applied Sciences
No full textThe aim of this study was to better evaluate the impact of on-site electro-generated hypochlorite for water disinfection. For this venture, the daily variability of hypochlorite-generating systems and their performance to produce low disinfection by-products during the formation of hypochlorite were observed. Seven on-site electro-generated hypochlorite installations, were selected at different swimming pool facilities in Switzerland. Active chlorine (AC), the two disinfection by-products chlorate (ClO3-) and perchlorate (ClO4-), and the pH were monitored over several hours. All monitored installations produced significant concentrations of chlorate, related to the measured active chlorine concentration. The median chlorate concentrations ranged between 1.4 to 76.9 µg ClO3-/mg AC during daily monitoring. Perchlorates have been detected only in the installations of one brand that generated concentrations up to 34.9 µg ClO4-/mg AC. For all installations, pH was lower than expected with a median pH of 9.6. Some samples presented even surprisingly acidic pH leading to possible sample degradation. This study clearly shows the weakness of a one-shot sampling to evaluate the quality of on-site electro-generated hypochlorite systems, due to high daily process variations. Additionally, the evaluation of the influence of three process parameters has pointed out that including chlorate aspects during the optimisation stage of on-site generated hypochlorite may significantly reduce chlorate contamination during water disinfection
The Effect of the Molecular Dipole and Quadrupole moments on Ion-Molecule Reaction Rates near 0 K
Get PDFWe review the results of our recent experimental and theoretical studies of gas-phase ion-molecule reactions involving the He+ ion at low collision energies (Ecoll), in the kB⋅(0 – 40) K range. To avoid heating of the ions by stray electric fields, the reactions are studied within the orbit of a Rydberg electron. We reach collision energies down to ~0 K by employing a merged-beam setup. In the case of a molecule with a dipole moment (e.g., ammonia), we observe a strong enhancement of the measured reaction yield with decreasing Ecoll. This enhancement is attributed to rotational states which experience linear negative Stark shifts in the electric field of the ion. When the molecule has no dipole moment but a negative quadrupole moment (e.g., N2), we observe a suppression of the total reaction yield at the lowest collision energy. Our results are interpreted with the aid of an adiabatic-channel model