ChemMedChem最新文献

A series of novel pyrazoline-based hybrids, bearing a pyrrole or indole scaffold, is designed, synthesized, and evaluated for anticancer potential. MTT assay reveals 4′a, 4′c, and 4′e as promising cytotoxic agents, where 4′e possess good pharmacological profile exhibiting prominent potency toward tumor cell lines HeLa, K562, and HL-60 (IC₅₀ = 3.7–5.1 µM), and selectivity toward normal MRC-5 cell line (IC₅₀ > 50 µM). Apoptosis induction is confirmed for all three compounds, with 4′e activating both caspase-3 and caspase-9 demonstrating a dual apoptotic mechanism. Molecular docking supports these findings, revealing a strong binding affinity of 4′e toward both caspases. Interaction with bovine serum albumin (BSA) is confirmed by fluorescence quenching and docking, indicating specific site binding and potential impact on pharmacokinetics. In addition, Förster resonance energy transfer (FRET) analysis provides valuable insight into the binding interaction between the investigated complexes and BSA. DNA-binding studies demonstrate that 4′e preferentially binds within the minor groove, while docking also suggests intercalative potential, which is further supported by viscosity measurements, confirming its ability to modulate DNA-dependent apoptotic signaling via intercalative binding. These results highlight compound 4′e as a promising anticancer candidate with selective cytotoxicity and multitarget engagement.

Beta-cyclodextrin (β-CD) metal complexes and their biomedical applications constitute an actively developing research field particularly in medicine. Herein, an iron/β-cyclodextrin (Fe(II)-β-CD) nanocomplex, synthesized at room temperature is characterized by various analytical techniques. The complex has a morphology of irregular-particles with an average of 4–10 nm, and displays a porous structure. In vitro, the particles are well-dispersible in the culture medium, which is typically an aqueous solution at pH = 7.4. The particles are stable under physiological conditions and biocompatible with living cells, making them a promising drug-delivery platform candidate. The Fe(II)-β-CD is screened for its anticancer potential against four types of malignant cell lines: liver(HepG2), breast(A549), lung(MCF7), and prostate(PC3) for the evaluation of prospective cytotoxicity properties. The results reveal that the nanocomplex show no cytotoxic effect. The dose response curves and the IC₅₀ of the sample on each cell line are evaluated at different incubation time intervals. The apoptotic mode of cell death is the prevailing mode after 24 and 48 h. Moreover, the molecular docking for the nanocomplex as an anticancer drug against the active site of CD44 glycoprotein (PDB-ID-1poz) is investigated. Based on the obtained results, the prepared complex paves the way for similar biomarkers in cancer treatment.

Minimolide, a sesquiterpene lactone isolated from Mikania minima, has displayed promising activity against Trypanosoma cruzi. The biocatalytic derivatization of minimolide and its analogs via selective acetylation and deacetylation is reported here using commercial lipases under mild and sustainable conditions. Reaction optimization identified Rhizomucor miehei lipase (RMIM) and Candida antarctica lipase B (CAL B) as the most efficient catalysts for acetylation and regioselective deacetylation, respectively. Structural transformations allow the synthesis of heliangolide and elemanolide analogs. The impact of the sesquiterpene lactone scaffold and acylation pattern on anti-Trypanosoma cruzi activity is evaluated in intracellular amastigotes. Compared to the parent compound, acetylated minimolide show enhanced antiparasitic activity (IC₅₀ =  1.08 µM) and a higher selectivity index (SI =  23.21). Likewise, acetylated heliangolide displayed improved selectivity as a result of reduced cytotoxicity. These findings underscore the usefulness of biocatalytic approaches in designing structurally optimized and more selective antitrypanosomal agents derived from natural lactones.

This study introduces a simple, eco-friendly, and biocompatible method for synthesizing hybrid antibacterial nanostructures using tryptophan-rich short peptide amphiphile (sPA). This sPA serve a dual role as both reducing and stabilizing agent for silver nanoparticles (AgNPs). Designed with self-assembling capabilities, the sPA spontaneously form polydispersed heterogeneous supramolecular nanostructures and simultaneously enable the in situ photoreduction of Ag(I) ions under mild sunlight exposure, owing to the intrinsic photophysical and redox-active properties of tryptophan residues. The resulting AgNP-sPA hybrids display well-defined polydispersed morphologies, confirmed through detailed spectroscopic and microscopic analyses. These nanoconjugates show excellent colloidal stability and strong interactions with bacterial membranes. Antibacterial assessments reveal that the AgNP-sPA hybrids exhibit potent and broad-spectrum activity against both Gram-positive (e.g., Staphylococcus aureus) and Gram-negative pathogens, including Escherichia coli (standard and clinical strains), Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Notably, the hybrids demonstrate superior efficacy compared to the conventional antibiotic levofloxacin. Importantly, the AgNP-sPA nanostructures also exhibit significant inhibitory activity against multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA), highlighting their potential in tackling antibiotic-resistant infections.

Helicobacter pylori exhibits a relatively high infection rate and marked drug resistance; in severe cases, it can even progress to gastric cancer, posing a substantial threat to human health. To address this pressing issue, the synthesis of a series of 1,4-naphthoquinone-benzenesulfonamide derivatives and investigations into their anti-H. pylori activity is reported.The synthesized compounds are characterized by ¹H/¹³C NMR and HRESIMS. Activity evaluation assays reveal that all synthesized compounds exert notable inhibitory effects against H. pylori, with minimum inhibitory concentrations ranging from 4 to 16 μg mL⁻¹ (positive control: metronidazole, 4 μg mL⁻¹). Compound 6i induces excessive reactive oxygen species (ROS) production in H. pylori, impairs mitochondrial structure and function, reduces ATP synthesis, and ultimately leads to bacterial death. The reduction of FADH₂ (a key donor for the electron transport chain), electron leakage, and the decreased NADP⁺/NADPH ratio further indicates that compound 6i can disrupt the intracellular redox balance in bacteria. Additionally, reverse transcription quantitative polymerase chain reaction experiments confirm that compound 6i downregulates the expression levels of ROS- and ATP-related genes. Furthermore, molecular docking and molecular dynamics simulation experiments verify that compound 6i can stably bind to the MdaB gene in H. pylori, thereby exerting a downregulatory effect on MdaB. Therefore, the synthesized compound 6i has been confirmed to be a compound capable of disrupting the redox balance and energy metabolism of H . pylori, and this compound may serve as a lead compound against H . pylori.

Tamoxifen, a selective estrogen receptor modulator, reduces fat mass and induces adipose tissue browning in obese mice, suggesting its potential as an antiobesity drug. However, small-molecule therapies often cause nonspecific side effects. The goal is to transport 4-hydroxytamoxifen (4-OHT) specifically into cells using the human neuropeptide Y (NPY) receptor type 1 (hY₁R), which is highly expressed on the surface of adipocytes. NPY conjugates are generated that link 4-OHT with three enzymatically cleavable and one self-immolative diamine linkers. All conjugates exhibit similar behavior regarding receptor activation and internalization. The activity of the intracellularly released 4-OHT is measured using a luciferase reporter gene assay. The diamine linker construct is the only conjugate that induces full reporter gene activation after internalization. However, the attachment of the drug to the peptide is unstable. Among peptides with enzymatically cleavable linkers, the conjugate with the GFLG linker exhibits the greatest reporter gene activity and is selected for further validation. A detailed analysis of its stability is performed using chromatography and mass spectrometry. Excellent plasma stability is demonstrated by fluorescence and isotopic labeling. These results demonstrate successful drug transport into target cells, paving the way for the further optimization of obesity therapies with reduced side effects.

Deuterated drugs offer longer action and lower market introduction costs. The current motivation for drug deuteration is primarily to slow metabolic processes. An alternative paradigm is proposed using binding isotope effects to minimize deuterium release, reduce peak drug concentrations linked to side effects, and extend the duration of the drug's active form. Identifying nonexchangeable hydrogen atoms with binding isotope effects less than unity through theoretical calculations is essential for this approach.

Herein, it is demonstrated that the addition of Lewis acids such as Zn(OTf)₂ to a large ionophoric natural product effects a fast cleavage of the molecule into two distinct fragments. The exploration of the mechanism implicates acidification of the carboxylic acid through metal coordination, and protonation of unbound molecules in a catalyzed cleavage; merck molecular force field (MMFF) conformational searches and density functional theory (DFT) calculations support these hypotheses. When a competing, more tightly binding metal such as K + is introduced, Zn(II) binding is precluded, and the rate of cleavage drops drastically. It is believed that these results may be helpful in understanding the role that metal ions play in drug degradation as well as illuminating their general role in altering the reactivity of ionophores.

The muscarinic acetylcholine receptor subtype M3 is validated as a promising target for imaging and therapy in breast cancer. Transcriptomic and proteomic profiling reveal its overexpression, particularly in triple-negative breast cancer. To overcome challenges in developing selective M3 inhibitors, fluorinated peptidomimetic compounds are designed featuring a β-alanine-glycine scaffold that mimics key M3 pharmacophore elements. These constructs show strong potential as lead structures for ¹⁸F-labeled positron emission tomography (PET) radioligands, as demonstrated with lead compound 24, exhibiting M3-selective binding (M1/M3, M2/M3, M4/M3, and M5/M3 > 45) with an IC₅₀ value of 0.3 μM. Compound [¹⁸F]24 is prepared as the first M3-selective PET radioligand using reductive amination with 4-[¹⁸F]fluorobenzaldehyde, in a 35% decay-corrected radiochemical yield. Radioligand [¹⁸F]24 is tested for PET imaging of M3 receptors in preclinical breast cancer models.

Dante Rotili, Domenico Tarantino, Vincenzo Carafa, Ester Lara, Sarah Meade, Giorgia Botta, Angela Nebbioso, Jörg Schemies, Manfred Jung, Aleksey G. Kazantsev, Manel Esteller, Mario F. Fraga, Lucia Altucci, Antonello Mai.

In the cited article Figures 3A and 3B should be substituted by the following (original data):

As depicted in Figure 3A, in the acetyl-p53 assay compound 5 and to a lesser extent, compounds 7 and 9 gave an appreciable signal increase relative to control, in agreement with their high SIRT1 inhibition. The other compounds were less or not effective in this test.

Regarding acetylation of α-tubulin (Figure 3B), a faint signal was observed with cambinol 1 and compound 10, whereas the other tested compounds did not elicit any acetyl-α-tubulin signal under these conditions.

With the new Figure 3, I declare that there are no changes to the previously described conclusions and that the scientific claims made in the original paper remain intact even with the replacement figures/new validating experiments.

Prof. Antonello Mai

Department of Drug Chemistry and Technologies

Sapienza University of Rome