ChemMedChem最新文献

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.

Following up on the discovery of multiple series of GPR39 antagonists via high-throughput screening (HTS), appropriate hit expansion and medicinal chemistry efforts lead to the identification of potent and selective GPR39 antagonists. Among these, compound 61 emerges as the front runner of this series, demonstrating high potency, appropriate physicochemical properties governing systemic exposure, in both rat and dog, and the absence of undesired off-target pharmacology such as cardiac ion channels (i.e., hERG, hNav1.5, and Cav1.2). In vivo evaluations show compound 61 to be a selective coronary vasodilator that reduced no-reflow and infarct size in a rodent model of ischemia-reperfusion. This first-in-class drug demonstrates the benefit of GPR39 inhibition in myocardial ischemia.

The spread of drug-resistant Plasmodium strains is diminishing the effectiveness of current antimalarials, highlighting the importance of discovering new therapeutics with novel targets. A screen of the Jumpstarter library against P. falciparum identified W482 with a pyrimidine-2,4-diamine scaffold. Structure-activity relationships reveal the importance of the pyrimidine core and its endocyclic nitrogen, while alternative amines are tolerated in the 4-position. Bulky and hydrophobic carboxamides or substituted phenyl ureas display the most potent antiplasmodial activity. Resistance selection and whole genome sequencing reveal an amplification of the gene encoding the ABCI3 transporter protein W482-resistant parasites. W482 is found to exhibit greater activity against parasites with reduced expression of ABCI3, confirming that resistance is related to the transporter. W482 arrests asexual parasites at the ring to trophozoite transition stage and exhibits a fast-killing profile with a lag phase of 24 h. Improving the antiparasitic activity alongside metabolic stability and solubility remains a challenge in the future development of the pyrimidine-2,4-diamine class.

It is estimated that more than 50% of marketed pharmaceuticals are derived from natural products. Structural characterization of natural products and their drug formulations is essential for the pharmaceutical industry. The use of microcrystal electron diffraction (MicroED) is reported to identify two polymorphic crystal structures of oxyacanthine dihydrochloride monohydrate from obfuscated samples that are mislabeled as “berbamine dihydrochloride”. The two polymorphs display primary conformational differences in one of the tetrahydroisoquinoline rings: one polymorph exhibits an intermediate conformation between half-chair and half-boat, while the other adopts a distinct half-boat conformation. Analysis of their structures, energies, and crystal packing diagrams indicates a thermodynamic preference for a transformation into the latter. This study highlights the value of integrating MicroED into pharmaceutical pipelines as an efficient tool for structural analysis and quality control.

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.

Female cancers, primarily breast, cervical, and ovarian cancers, remain a major public health challenge, with rising incidence and high mortality. Cisplatin has long been a cornerstone of anticancer therapy, yet its clinical use is limited by low selectivity, severe side effects, drug resistance, and relapse. Thus, more effective and selective therapeutic strategies are needed. In this study, we evaluated the cytotoxicity and mechanisms of action of three cisplatin derivatives (C-cisplatin, D-cisplatin, and Ac-cisplatin) and their complexes with generation 2 polyamidoamine (PAMAM G2) dendrimers. All drug–dendrimer complexes were prepared at a 10:1 molar ratio and tested on two cancer cell lines—HeLa (cervical cancer) and MCF-7 (breast cancer)—and one non-cancer human microvascular endothelial cell line (HMEC-1). Complex formation was confirmed by zeta potential measurements. Cytotoxicity was assessed for both free and complexed drugs. To explore potential mechanisms of action, mitochondrial membrane potential and reactive oxygen species (ROS) levels were evaluated. Flow cytometry was then used to determine dominant cell-death pathways. The complexes demonstrated cytotoxicity comparable to or greater than cisplatin and showed improved selectivity toward cancer cells. Among them, D-cisplatin complexed with PAMAM G2 was the most promising candidate, exhibiting the highest selectivity toward HeLa cells.

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).