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Bioactive compositions containing vanadium complexes have been a viable strategy for constructing more biocompatible and less toxic systems. Therefore, this work aim to develop a new composition formed by an oxidovanadium(IV) complex as levan. The acute oral toxicity and insulin resistance (IR) are investigated in an animal model using adult Swiss mice treated with daily injections of the synthetic glucocorticoid dexamethasone. The complex is characterized by electronic absorption (λ_max = 771 and 880 nm) and infrared spectroscopies (3359, 3167, 1606, 1342, 1072 cm^-1, and the VO at 937 cm^-1); NMR of the ¹H, ¹³C, and ⁵¹V (-427, -509, and -529 ppm), and electron paramagnetic resonance (g-factor = 1.985). The vanadium complex is classified in category 4, according to the acute toxicity protocol. IR in mice is accompanied by a rise in fasting blood glucose at seventh (2.2-fold) and 14th (threefold) days, triglyceride levels at seventh (2.6-fold) and 14th (threefold) days, and triglyceride/glucose index (TyG) at seventh (20%) and 14th (25%) days. The bioactive composition attenuated both the hyperglycemia (≈65%) and hypertriglyceridemia and TyG in a dose-dependent manner. The proposed composition shows promise in reducing IR induced by exogenous corticosteroid treatment.

A straightforward method for creating C(sp²)-C(sp³) bonds is employed to develop novel cereblon (CRBN) E3 ligase ligands, essential for targeted protein degradation (TPD) applications. While most prior studies focus on biological activities, this work explores how the linker attachment and bond types affect physicochemical stability, binding affinity, and degrading performance. Utilizing N-hydroxyphthalimide (NHP) esters and aryl bromides, a resilient decarboxylative cross-coupling technique that broadens the available chemical space beyond traditional C(sp²)-N connections is developed. Several well-established and underexplored CRBN binders and their derivatives are synthesized and studied. Binding affinity, aqueous solubility, stability in microsomes, and degradation of typical CRBN ligand off-targets are then investigated. Selected compounds are transformed into GSPT1-targeting molecular glue degraders or BRD4-targeting proteolysis-targeting chimeras (PROTACs). Benzamide-based degraders obtained using the new method have a very high ability to break down BRD4. This research shows that C(sp²)-C(sp³) connections open up new ways to fine-tune PROTAC characteristics, which unlock degrader chemotypes that were not accessible before. The results demonstrate the importance of synthetic innovation in developing ligands for TPD applications.

pH-sensitive liposomes represent a promising platform for targeted drug delivery, with imidazole-based lipids offering unique advantages for tumor-specific release and enhanced endosomal escape. This pH-responsiveness facilitates cellular uptake through electrostatic interactions and improves intracellular delivery, primarily via the proton sponge effect and membrane fusion mechanisms. This article provides a comprehensive overview of imidazole-modified liposomes, detailing their pH-responsiveness mechanisms, diverse formulations, and highlighting current gaps and future research directions within the field. Special attention is given to the characteristics, advantages, and applications of key structures, including imidazole-lipid compounds, imidazole-cholesterol conjugates, and histidine-bearing polymers. The incorporation of imidazole has been shown to optimize drug release profiles, enhance intracellular delivery, and improve cytotoxicity toward cancer cells, while maintaining a favorable safety profile under physiological conditions comparable to conventional liposomes. Recent advancements highlight the impact of structural modifications, such as carbon chain length optimization, conjugated moieties, and polymer architecture, on modulating liposome stability, drug release kinetics, and targeting efficiency. Despite these notable advancements, significant challenges persist, including the critical balance between carrier stability and pH sensitivity, immune clearance, endosomal entrapment, and the complexities associated with large-scale synthesis.

Assessing if compounds with intracellular targets reach their site of action is crucial for success in drug development. Cell type-specific uptake goes beyond permeability studies, typically mimicking crossing the gut, the lung, or the blood-brain barrier. A medium- to high-throughput cellular accumulation protocol in 96-well format is presented using six compounds, evaluating optimal conditions varying several parameters, such as incubation time, compound concentration, and extraction protocol. An optimized assay protocol for cellular accumulation of distinct chemical classes is a compromise: No one-extraction-protocol-fits-all exists; equally, some compounds need longer incubation periods to reach maximal intracellular concentration. Reliable high performance liquid chromatography with tandem mass spectrometry based quantification of cellular accumulation for all six compounds to the nM range is achieved with a short 1 h incubation. Intracellular concentrations per cell count are determined in A549^ACE+TMPRSS2 cells, taking nonspecific binding into account. Hence, this approach adds valuable information during the pre-screening of compounds with intracellular targets. Finally, optimal assay conditions are emphasized as essential for predicting activity in vitro and in vivo, based on biochemical information and intracellular concentrations. In summary, the workflow for cellular accumulation determination can serve two scenarios: 1) Pre-selection of compounds for screening purposes or 2) systematic optimization of conditions to advance compounds with intracellular targets.

One of the major mechanisms of resistance to ribosome-targeting antibiotics is the modification of ribosomal RNA (rRNA). Specific methyltransferase enzymes, for example, confer high-level resistance to aminoglycosides by selectively methylating the 16S rRNA in the ribosomal decoding center. These enzymes have been detected globally and pose a threat to the continued use of aminoglycosides. Compound 1, a dehydroamino amide inhibitor of the m¹A1408 methyltransferase NpmA, was previously disclosed and identified using high-throughput virtual screening. Here, the synthesis and biological evaluation of rationally designed analogs of 1 has been reported. Guided by molecular docking, additional putative inhibitors of NpmA, as well as the functionally related m⁷G1405 methyltransferase RmtB, varying in each region of the original scaffold are disclosed. A modular, fragment-based synthesis enables access to 17 analogs, which exhibits mixed activity against NpmA and RmtB, including several that are selective for RmtB. The structure-activity relationship determined for the dehydroamino amide series will guide continued research against this target class with the aim of developing a toolkit for selective- or pan-16S rRNA methyltransferase inhibition.

Imagine a divalent metal ion (such as Zn(II)) binding to a folded ionophore such as salinomycin. The resulting complex is superacidified, shooting a proton at an unbound salinomycin molecule and cleaving it into two parts. However, when potassium ion is prebound to salinomycin, no superacidic protons are generated by this complex, whereas the protons generated by the divalent metal ion complex just bounce off. More details can be found in the Research Article by Adam Huczyński, Travis Dudding, Thomas Lectka, and co-workers (DOI: 10.1002/cmdc.202500783).

Novel tetrahydroindolone dihydropyrimidinone hybrid compounds exhibited significant antibiofilm activity against resistant bacterial Staphylococcus aureus and Pseudomonas aeruginosa strains, indicating molecular hybridization played crucial role to this performance. Toxicity studies using Caenorhabditis elegans model revealed no observable toxicity, even at elevated concentrations. Combination of strong antibiofilm activity with non-toxic behavior underlines the antivirulence potential, positioning the hybrid compounds as promising adjuvants in the fight against chronic bacterial infections. More details can be found in the Research Article by Karine R. Zimmer, Dennis Russowsky, and co-workers (DOI: 10.1002/cmdc.202500716).

In the present study, eight novel substituted 4-cyano-N-(4-cyano-1,3-oxazol-5-yl)-N-alkyl-1,3-oxazole-5-sulfonylamides have been synthesized. Compounds are characterized by IR, ¹H, ¹³C NMR spectroscopy, elemental analysis, and chromato-mass-spectrometry. The anticancer activities of six compounds are evaluated against the NCI-60 human tumor cell line panel. The tested compounds exhibit the strongest antiproliferative (TGI) and cytotoxic (LC₅₀) activities within the leukemia, non-small-cell lung cancer, melanoma, and colon cancer subpanels. Overall, the mean activity parameters (GI₅₀, TGI, and LC₅₀) calculated for three compounds do not differ significantly and are within the range of 1-100 µM, and for some lines, it reaches the value 10^-8 mol L^-1. Structure-activity relationship analysis reveals markedly higher activity for bisoxazole derivatives bearing 4-MeC₆H₄ or 4-FC₆H₄ at the second position of the oxazole rings (compounds 2, 3, and 7), whereas derivatives with diphenyl, di-tolyl substituents (compounds 1 and 6), or 4-ClC₆H₄ (compound 8) exhibit substantially lower anticancer activity. In addition, the potential molecular mechanisms of anticancer action of these compounds are investigated using molecular docking methods. Derivatives show the highest affinity for tubulin and cyclin-dependent kinases. Docking of 4-cyano-N-[4-cyano-2-(4-fluorophenyl)-1,3-oxazol-5-yl]-N-methyl-2-(4-methylphenyl)-1,3-oxazole-5-sulfonamide into the colchicine-binding site of αβ-tubulin reveals a binding affinity of -10.9 kcal mol^-1, with the ligand located at the subunit interface.

This work explores the toxicity profile and anticancer mechanisms of reported anti-HIV carboxyphenyl porphyrin–fullerene dyads, PB₃C₆₀ and PB₃C₇₀, together with their precursor porphyrin PB₃OH, within noncationic porphyrin-based donor–π–acceptor (D–π–A) assemblies. This study evaluates the patented compounds meso-tris-p-carboxyphenyl porphyrin-fullerene (P-F) dyads, PB₃C₆₀ and PB₃C₇₀, and precursor PB₃OH within noncationic donor–π–acceptor (D–π–A) assemblies as amphiphilic photosensitizers (PSs) for glioblastoma photodynamic therapy (PDT). Emphasis is placed on light-induced apoptosis, mitochondrial disruption in glioma-derived cells, along with the already reported anti-HIV properties, indicating potential for dual-action therapy in immunocompromised individuals. Given the critical need for therapies effective in immunocompromised patients, further investigation into noncationic P-F dyads could yield dual-action agents. P-F dyads were administered to tumour-derived as well as nontransformed cells and subjected to PDT. PB₃C₆₀ exhibited the highest selective phototoxicity in gliomblastoma cells under PDT, inducing apoptosis with moderate ROS and mitochondrial fragmentation. PB₃OH caused nonspecific cytotoxicity via excessive ROS, while PB₃C₇₀ triggered apoptosis even without light. PB₃C₆₀ showed strong potential as a targeted photosensitizer for glioblastoma, with light-dependent selectivity for cancer cells. Unlike PB₃OH and PB₃C₇₀, its apoptotic effect was both specific and light activated, highlighting PB₃C₆₀'s promise as a nanohybrid therapeutic for glioblastoma.

Inhibitors of the 90- kDa heat shock protein (Hsp90) family, especially Hsp90β, have been a sought-after therapeutic strategy for the treatment of cancer, neurological disorders, and other diseases. Furthermore, recent studies suggest that their coadministration with other therapies can enhance efficacy. pan-Inhibition of the cytosolic Hsp90α and Hsp90β isoforms has proven to be problematic, since the on-target toxicities have resulted in the failure of most Hsp90 inhibitors that entered clinical trials. Consequently, such outcomes highlight the demand for isoform-selective inhibitors that overcome these detriments. Previously, we reported that subtle modifications to the solvent-exposed region of Hsp90β-selective inhibitors can significantly impact affinity and selectivity. Consequently, nineteen additional analogs were synthesized and evaluated for their ability to bind the cytosolic Hsp90 isoforms, as well as elucidate further structure–activity relationships (SAR) at this region of the molecule. The work herein reveals the extent to which appendages with steric bulk are tolerated, as well as the importance of heteroatoms to maintain high Hsp90β affinity and selectivity. Biological evaluation of these compounds supports the selective inhibition of Hsp90β in cellulo, which is encouraging for the continued exploration of Hsp90 isoform-selective inhibitors for therapeutic applications.