ChemMedChem最新文献

The human 2-oxoglutarate-dependent oxygenase Jumonji-C domain-containing protein 6 (JMJD6) catalyzes post-translational C-5 lysyl residue hydroxylation in multiple proteins. Aberrant JMJD6 catalysis is associated with the upregulation of androgen receptor splice variant 7 (AR-V7), which confers resistance towards antiandrogens used for prostate cancer treatment; JMJD6 is thus a promising cancer target. To date, few small-molecule JMJD6 inhibitors are reported, likely in part reflecting a lack of robust assays to monitor effects of small molecules on catalysis by isolated JMJD6. The use of solid-phase extraction coupled to mass spectrometry assays is described to screen scaffolds for the development of selective JMJD6 inhibitors. The results reveal that the reported JMJD6 inhibitors WL12, SKLB325, and Compound 7p manifest relatively inefficient JMJD6 inhibition in vitro. By contrast, some, but not all, clinically used inhibitors of the human hypoxia-inducible factor-α prolyl hydroxylase domain-containing proteins (PHDs) efficiently inhibit isolated JMJD6, in particular Enarodustat and Desidustat. The results identify attractive scaffolds for the development of selective, cell permeable JMJD6 inhibitors and suggest that JMJD6 inhibition is a potential off-target effect of PHD inhibitors in clinical use.

The inflammatory cascade of acute kidney injury (AKI) is mainly mediated by TLR-4/NF-κB signaling pathway that ultimately leads to increased release of proinflammatory cytokines. This study aims to discover novel anti-inflammatory candidates targeting proinflammatory cytokines in AKI. Ten novel coumarin-ferulate cyclic conjugates (1–10) are synthesized (by oxidative coupling of coumarin derivatives and ethyl ferulate) and characterized (mass and nuclear magnetic resonance spectroscopy). All compounds are tested for cytotoxicity and proinflammatory cytokines inhibition properties using RAW 264.7 cells stimulated with lipopolysaccharide (Enzyme Linked Immuno-Sorbent Assay). The compounds 3 and 5 show excellent inhibition of TNF-α, IL-6, and IL-1β secretions and also inhibite IL-1β protein levels (western blot). Compounds 3 and 5 are then evaluated (50 mg kg⁻¹ oral dose; C57BL/6 mice) in an oxalate-induced nephropathy model. Results show significant renal protection in compound-treated animals, as evidenced by a significant decrease in the blood urea nitrogen and creatinine, IL-1β protein expression (western blot), and mRNA levels of TNF-α and IL-1β (real-time polymerase chain reaction)). A decrease in the overall percentage of live immune cells and kidney resident macrophages in renal tissues is also observed (flow cytometry). Additionally, histopathological studies (H&E staining) show a significant decrease in renal tissue damage (tubular injury index). This findings suggest that these new anti-inflammatory conjugates have a strong renal protective effect.

Proteolysis-targeting chimeras (PROTACs) have emerged as an excellent strategy for targeted protein degradation by the ubiquitin-proteasome system. Traditional inhibitors suppress the enzymatic activity, but the PROTACs utilize the method of total degradation of protein, promising prolonged and target-specific therapeutic efficacy. Histone deacetylases (HDACs) are epigenetic regulators, implicated in most cancers, neurodegeneration, and other inflammatory diseases. Therefore, HDAC-PROTAC development provides a unique approach to overcome the limitations of conventional HDAC inhibitors, including off-target effects, short duration of action, and resistance mechanisms. Recent advancements in HDAC-PROTACs lead to the design of selective degraders for specific isoforms of HDACs, including HDAC3, HDAC4, HDAC6, and HDAC8, representing superior efficacy in preclinical studies. This review highlights the progress of HDAC-targeting PROTACs, focusing on structural optimization, selectivity enhancements, and therapeutic applications with their degradation potential. However, various challenges include poor pharmacokinetics and bioavailability, and limited in vivo validation for further safety, efficacy analysis. Further research and optimization efforts will be pivotal in translating HDAC-PROTACs into clinically viable therapies for cancer and other epigenetic disorders.

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.