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Superparamagnetic iron oxide nanoparticles (SPIONs) exhibit unique properties for diverse biomedical applications, including drug delivery and diagnostic imaging. Actively targeted SPIONs enhance delivery to diseased sites, reducing side effects and enhancing treatment efficacy. However, development of reproducible functionalization protocols is challenged by the erratic behavior of nanoparticles in suspensions, such as agglomeration and sedimentation. In this study, we develop and systematically optimize a functionalization method to attach the Fc-region of antibodies onto silica coated SPIONs via click chemistry, ensuring controlled ligand orientation on the particle surface. The synthesis and successive modifications of silica coated SPIONs with organic moieties is presented resulting in the final click conjugation with anti-ICAM1 antibodies. These antibodies target ICAM1, upregulated on epithelial cell surfaces during gastrointestinal inflammation. Thermogravimetric analysis and infrared spectroscopy confirm successful SPION functionalization after each modification step. Cell viability assessment indicates no adverse effects of bioconjugated particles. Quantitative elemental analysis reveals significantly higher iron concentration in inflammation-induced Caco-2 cells exposed to ICAM1-modified particles compared to non-conjugated counterparts. Furthermore, laser scanning confocal microscopy of these cells suggests surface interaction and internalization of bioconjugated SPIONs, underscoring their potential for targeted imaging and therapy in inflammatory diseases.

Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-beta-lactamases is of particular concern as these bacterial enzymes dismantle most beta-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-beta-lactamase inhibitors are available. Aiming to adapt to structural variations, we introduce the inhibitor concept: dynamically chiral phosphonic acids. We demonstrate that they are straightforward to synthesize, penetrate bacterial membranes, inhibit the metallo-beta-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of beta-lactam hydrolysis, they target the Zn ions of the metallo-beta-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-beta-lactamases, which provides them unparalleled adaptability to the structural diversity of these enzymes, and may allow them to hamper bacteria's ability for resistance development.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the regulation of blood cholesterol levels. Its inhibition attenuates hypercholesterolemia and hence is a viable approach for the management of atherosclerotic cardiovascular disease (ASCVD). We evaluated the flavonoids of the leaves of Monanthotaxis filipes P.H. Hoekstra (Annonaceae) for their effect on PCSK9 and low-density lipoprotein receptor (LDLR) expression at the mRNA level in HepG2 cells using quantitative real-time PCR analysis and for their influence on protein expression by ELISA. Six flavonoids, including two chalcones (1, 5), three flavones (2–4), and one flavanone (6), were isolated by chromatographic techniques and identified by spectroscopic (NMR, IR, UV, MS) analyses. 2′,3′,4′,6′-Tetramethoxychalcone (1) reduced the PCSK9 protein amount and altered LDLR both on mRNA and protein levels, 6,7,8-trimethoxyflavone (2) inhibited PCSK9 both on mRNA and protein levels but did not change the amount of LDLR in HepG2 cells, whereas 2ʹ,4ʹ-dihydroxy-6ʹ-methoxy-3ʹ,5ʹ-dimethylchalcone (5) decreased PCSK9 and upregulated LDLR protein expression. Thus, chalcones 1 and 5, flavones 2–4, and flavanone 6 were shown to be promising compounds for the management of cardiovascular disease. Molecular dynamics simulations suggest that an allosteric mechanism underlies the inhibitory effect of 2 on PCSK9. In contrast, the pronounced activity of 5 is due to the interaction of its benzene ring with the Cys358, Pro438, Val460 and Trp461 residues of the catalytic site, as proposed by Molecular Mechanics Poisson Boltzmann surface area (MM-PBSA) analyses. Our results showed that chalcone 5 might be studied further for the management of atherosclerotic cardiovascular disease (ASCVD).

The ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments.

Three new dihydroflavonols, gloverinols A–C (1–3), a new flavon-3-ol, gloverinol D (4), two new isoflavans, gloveriflavan A (5) and B (6), and seven known compounds were isolated from the root bark of Dalbergia gloveri. The structures of the isolates were elucidated by using NMR, ECD, and HRESIMS data analyses. Among the isolated compounds, gloverinol B (2), gloveriflavan B (6), and 1-(2,4-dihydroxyphenyl)-3-hydroxy-3-(4-hydroxyphenyl)-1-propanone (10) were the most active against Staphylococcus aureus, with MIC values of 9.2, 18.4, and 14.2 μM, respectively.

Three new (1–3) and six known rotenoids (5–10), along with three known isoflavones (11–13), were isolated from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14–18), and one known chalcone (19) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC₅₀ values of 0.7 and 3.4 μg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC₅₀ values of 0.4–10 μM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC₅₀ of 4.2 μM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3, 11, and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.

The phytochemical investigation of the leaves and the roots of Suregada procera afforded the new ent-abietane diterpenoid sureproceriolide A (1) along with the known secondary metabolites 8,14β:11,12α-diepoxy-13(15)-abietane-16,12-olid (2), jolkinolide A (3), jolkinolide E (4), ent-pimara-8(14),15-dien-19-oic acid (5), sitosterol (6), oleana-9(11):12-dien-3β-ol (7), and oleic acid (8). Their structures were elucidated by NMR spectroscopic and mass spectrometric analyses, and the structure of jolkinolide A (3) was confirmed by single-crystal X-ray diffraction analysis. Sureproceriolide A (1) showed modest activity against the Gram-positive bacterium Staphylococcus lugdunensis (MIC = 31.44 μM), and sitosterol (6) against the Gram-negative bacterium Porphyromonas gingivalis (IC₅₀ = 45.37 μM). Jolkinolide A (3) and E (4) as well as sitosterol (6) inhibited the release of NOS (IMR-90 cells), TNF-α (HaCaT cells) and NF-κB (HaCaT cells), with IC₅₀ values of 0.43, 3.21, and 10.32 μM, respectively. Compound 6 showed antitumoral activity against SK-MEL-28 (IC₅₀ = 20.66 μM) and CCD-13Lu (IC₅₀ = 24.70 μM) cell lines, with no cytotoxic effect against the prostate cells PrEC (CC₅₀ > 300 μM).

For a comparison of the interaction modes of various chalcogen-bond donors, 2-chalcogeno-imidazolium salts have been designed, synthesized, and studied by single crystal X-ray diffraction, solution NMR and DFT as well as for their ability to act as activators in an S_N1-type substitution reaction. Their interaction modes in solution were elucidated based on NMR diffusion and chemical shift perturbation experiments, which were supported by DFT-calculations. Our finding is that going from lighter to the heavier chalcogens, hydrogen bonding plays a less, while chalcogen bonding an increasingly important role for the coordination of anions. Anion-pi interactions also show importance, especially for the sulfur and selenium derivatives. The noncovalent interaction modes of 2-chalcogeno-imidazolium salts have been studied in the solid state, in solution by DOSY, NMR titration and activation experiments, as well as in silico. A combined anion-pi /chalcogen bonding interaction mode prevails for most compounds. For the tellurium derivatives, the pure chalcogen bonding gains in importance, while hydrogen bonding becomes more relevant for the sulfur analogs. image

A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools. Subsequently, we describe cuttingedge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.

Bacterial resistance to the majority of clinically used ll-lactam antibiotics is a global health threat and, consequently, the driving force for the development of metallo-ll-lactamase (MBL) inhibitors. The rapid evolution of new MBLs calls for new strategies and tools for inhibitor development. In this study, we designed and developed a series of trifluoromethylated captopril analogues as probes for structural studies of enzyme-inhibitor binding. The new compounds showed activity comparable to the non-fluorinated inhibitors against the New Delhi Metallo-ll-lactamase-1 (NDM-1). The most active compound, a derivative of D-captopril, exhibited an IC50 value of 0.3 mu M. Several compounds demonstrated synergistic effects, restoring the effect of meropenem and reducing the minimum inhibitory concentration (MIC) values in NDM-1 (up to 64-fold), VIM-2 (up to 8-fold) and IMP-26 (up to 8-fold) harbouring Escherichia coli. NMR spectroscopy and molecular docking of one representative inhibitor determined the binding pose in NDM-1, demonstrating that fluorinated analogues of inhibitors are a valuable tool for structural studies of MBL-inhibitor complexes.