ChemMedChem最新文献

The proteasome is a central component of the cellular machinery responsible for degrading misfolded or damaged proteins, thereby maintaining protein homeostasis. Dysregulation of proteasome activity has been implicated in various diseases, including neurodegenerative disorders and cancer. In this article, a new β-cyclodextrin conjugate of suxibuzone (SB-CD) is designed and its proteasome activity on purified human 20S core particle and in differentiated human neuroblastoma SH-SY5Y cells (dSHSY5Y) is investigated. This conjugate enhances the proteolytic activity of the 20S proteasome in a dose-dependent manner, with an increase observed at concentrations as low as 5 µM. The EC50 values for SB-CD are determined to be 0.6 ± 0.1 µM for chymotrypsin-like activity and 1.1 ± 0.3 µM for trypsin-like activity, indicating higher efficacy compared to suxibuzone alone. In dSH-SY5Y cells, a decrease in the accumulation of ubiquitinated proteins is observed, consistent with the activation of the proteasome. High-resolution electrospray ionization mass spectrometry investigations confirmed the internalization of SB-CD in cells and verified the stability of the conjugate in response to cellular protease effects, after incubation for up to 24 h. These promising results suggest that the new conjugate is an effective enhancer of proteasome activity, holding significant promise for therapeutic applications targeting proteasome-related pathologies.

Zinc complexes have promising possibilities as medicines since they have better efficacy and lower toxicity. Herein, two ligands are synthesized based on hydrazine-1-carbothioamide with substituents having different electronic nature {nitro (HNPhHCT) and methoxy (HMoPhHCT)} and their respective Zn(II) complexes {[Zn(NPhHCT)₂] and [Zn(MoPhHCT)₂]}. They have been fully characterized via several spectroscopic techniques (IR, NMR, HRMS, UV–Vis studies) and DFT studies. In addition, ligands and their respective complexes are screened for their antiproliferative activity against three different cancer cell lines, namely HuT-78 (T-cell lymphoma), DL (Dalton's lymphoma), and MCF-7 (Breast cancer) cell lines. Among the two complexes, [Zn(MoPhHCT)₂] is found to be most cytotoxic on all three cancer cell lines. In HuT-78 cells, [Zn(MoPhHCT)₂] exhibited IC₅₀ value at ≈4 µM. Further, glucose and ROS estimation assays suggested that [Zn(MoPhHCT)₂] shows antiproliferative activity against T lymphoma cells by inhibiting their glycolytic activity and apoptosis induction by increasing ROS production. A molecular docking study is performed against an antiapoptotic protein, BCL2 (PDB: 2O2F), that confirms its inhibitory response with a binding score of −8.34 kcal mol⁻¹. Further, the expression of BCL2 at the protein level is found to be significantly inhibited in response to treatment with [Zn(MoPhHCT)₂], as evident by the Western blot analysis results.

In recent years, developing effective theranostic agents for precise cancer treatment has been one of the most prevalent strategies. Herein, three staurosporine derivatives, MCY-STS, ECY-STS, and ICY-STS, synthesized through minor modifications of natural staurosporine, are reported. These derivatives not only exhibit attractive fluorescence properties, including solvatochromism and dual-state (solution and solid) emission, but also demonstrate potent protein kinase C inhibitory activity and anticancer effects against NCI-N87, MCF-7, and SK-OV-3 cell lines. Theoretical calculation analyses, including density functional theory calculations, molecular docking, and molecular dynamics simulations, are employed to elucidate their protein–ligand interactions and luminescence mechanisms. Further investigations reveal that ECY-STS significantly inhibits tumor growth while illuminating tumor tissues for therapy visualization. Collectively, these modified fluorescent staurosporine derivatives, particularly ECY-STS, represent promising theranostic agents that provide a novel strategy for cancer imaging and treatment in humans.

The cover art illustrates the Cobalt–Chrysin Prodrug (CCP), engineered for targeted cancer therapy. On the left, cobalt(III) binds to chrysin, masking its cytotoxicity under normal conditions. The right half depicts CCP activation in the hypoxic tumor environment, releasing chrysin, which then interacts with biomolecules in cancer cells to generate reactive oxygen species (ROS) and induce apoptosis. The bright bursts symbolize selective cancer cell death, highlighting CCP′s potential as a promising anticancer therapeutic for tumor-specific destruction. More details can be found in the Research Article by Rakesh Kumar Pathak and co-workers (DOI: 10.1002/cmdc.202500232).

The anticancer potential of silver(I) metallodrugs incorporating mefenamic acid and mitochondriotropic agents in 3D spheroid models of hormone-dependent breast cancer cells (MCF-7) is investigated within this work. The compounds, previously evaluated in 2D cultures, demonstrated potent antiproliferative activity with IC₅₀ values ranging from 1.01 to 5.20 μM, significantly outperforming cisplatin. Here, 3D spheroids are employed to simulate the tumor microenvironment, assessing drug efficacy through morphological changes and apoptosis rates. Compounds 1–4 exhibited dose- and time-dependent reductions in spheroid compactness and sphericity, with compound 2 achieving complete loss of compactness (0%) and sphericity (2%) at 10 μM after 48 h. Apoptotic activity is also significantly higher in 3D spheroids treated with these compounds with respect to their control (25.8%−41.4%), in contrast to cisplatin (24.4%) and untreated cells (8.0%). The results validate the superior efficacy of silver(I) complexes in disrupting tumor integrity and inducing apoptosis. This study underscores the potential of 3D spheroid models for preclinical evaluation and highlights silver(I) metallodrugs as promising candidates for breast cancer therapy. Future research should focus on in vivo validation to further explore their therapeutic applications.

A series of 2-iminothiazolidin-4-one–1,3,4-thiazole hybrids 7a–l are synthesized and screened for their inhibitory activities against responsible enzymes in type 2 diabetes mellitus (T2DM) and Alzheimer's diseases. Among the compounds with potential inhibitory activity, several 2-iminothiazolidin-4-ones exhibit the strongest inhibitory activity against the screened enzymes, including 7c (IC₅₀ = 6.12 ± 0.11 µM, for α-amylase), 7e (IC₅₀ = 6.78 ± 0.15 µM, for α-glucosidase), 7k (IC₅₀ = 1.82 ± 0.04 µM, for DPP-4), 7f (IC₅₀ = 2.21 ± 0.02 µM, for PTP1B), 7h (IC₅₀ = 0.06 ± 0.01 nM, for AChE), 7j (IC₅₀ = 0.03 ± 0.01 nM, for BChE, and IC₅₀ = 0.32 ± 0.01 nM, for MAO-A), and 7l (IC₅₀ = 0.02 ± 0.01 nM, for MAO-B). Compound 7j exhibits the strongest inhibitory activity for both BChE and MAO-A. Compounds with short-chain alkyl groups (2–4 carbon atoms) have the strongest inhibitory activity against the enzymes responsible in T2DM, with the exception of 7k (with 6-carbon atom chain), whereas the long-chain alkyl groups (with 5–7 carbon atom chains) have the strongest inhibitory activity against the enzymes responsible in Alzheimer's disease. These compounds also exhibit the high antiglycation and antioxidant activity in DPPH and ABTS^•+ scavenging assays. They are noncytotoxic for WI-38 cell line with IC₅₀ > 76 μM.

Cancer remains a major global health challenge, with resistance to existing therapeutic regimens underscoring the development of novel agents with improved efficacy and reduced toxicity. The indole and 1,3,4-thiadiazole scaffolds are distinguished for their broad-spectrum bioactivities, including anticancer properties. In this study, the synthesis and biological evaluation of a new series of indole-1,3,4-thiadiazole Schiff bases (U1-U31) designed to enhance anticancer efficacy is explored. In vitro evaluation demonstrates potent and selective cytotoxicity of several compounds, particularly U19 and U24, against multiple cancer cell lines, with minimal toxicity to normal cells. Molecular docking and density functional theory studies demonstrate that these hybrid compounds effectively occupy the ATP-binding sites of Pi3K and Akt proteins, exhibiting notable binding interactions comparable to the respective standard inhibitors. In addition, molecular dynamics simulation is performed to understand the conformational changes of the protein–ligand complex. Overall, the findings indicate that these novel indole-1,3,4-thiadiazole derivatives have selective inhibitory potency, making them promising leads for further anticancer drug development.

Organic light-emitting diodes (OLEDs) with dual emission in the red and near-infrared regions offer a breakthrough opportunity for simplifying pulse oximetry technology. Here, a new class of bimetallic complexes Eu_0.1Yb_0.9(L)₃Q (L = β-diketonates; Q = neutral ligands) with simultaneous emission at 612 and 978 nm has been reported, optimized for solution-processed OLEDs. A device based on Eu_0.1Yb_0.9(dbm)₃thiadiazolophenanthroline (TDZP) exhibits the highest electroluminescence intensity in both spectral ranges and is employed as a single-pixel light source in a custom-built pulse oximeter prototype. The prototype demonstrates real-time measurement of heart rate and blood oxygen saturation in full agreement with commercial devices. This is the first demonstration of a fully functional OLED-based oximeter relying on dual-emissive lanthanide complexes. This results pave the way for next-generation wearable biomedical sensors using advanced emissive materials and simplified device architectures.

Sickle cell disease (SCD) is a debilitating inherited blood disorder characterized by acute crises that require immediate intervention. Aromatic aldehydes that increase hemoglobin (Hb) oxygen affinity (e.g., 5-HMF) can prevent hypoxia-induced erythrocyte sickling, but clinical efforts have been hindered by insufficient potency or poor pharmacokinetics. Herein, analogs of 5-HMF (MMA-500 series of compounds) are reported to retain 5-HMF positive physicochemical and pharmacodynamic properties, including safety, solubility, and relatively short duration of action that are essential for their acute use. Two analogs, MMA503 and MMA509, demonstrate over 3.3-fold greater in vitro antisickling activity than 5-HMF. This potency is evidenced by significantly enhanced Hb adduct formation, increased oxygen affinity, and robust inhibition of red blood cell sickling in sickle blood assays. X-ray crystallography further elucidates the Hb binding interactions underlying their potency at the molecular level. MMA509 emerges as a lead candidate and is advanced to formulation studies. An IV formulation of MMA509 in 40% polyethylene glycol 400 achieves ≈13.5 mg mL⁻¹ solubility, enabling rapid attainment of therapeutic drug levels. The potent pharmacologic profile of MMA509, combined with its successful parenteral formulation, highlights its promise as a fast-acting therapeutic for acute SCD crises as a result of rapid onset expected from IV dosing.

The development of a phospholipid bilayer coating on the nanoparticle surface, particularly mesoporous nanosilica (MSN), has recently emerged as a promising strategy in drug delivery systems. However, the strong interactions of the phospholipid bilayer promote the adsorption of plasma proteins onto nanocarriers, leading to physicochemical instability and undesired aggregation. This study explores the use of polyoxyethylene alkyl ether (Brij), a PEG-based surfactant, to enhance the stability of phospholipid bilayer-coated MSN in serum environments. Initially, Brij-coated liposome (LB), a type of phospholipid-based nanoparticles, is synthesized via the thin film hydration method. The LB is subsequently immobilized onto the MSN surface to form Brij-coated MSN-liposome nanoparticles (MLB). The physicochemical properties and morphology of MLB are characterized through Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, Brunauer−Emmett−Teller, scanning electron microscopy, transmission electron microscopy, and dynamic light scattering. The Brij-coated MLB exhibited significantly improved stability in serum environments compared to MSN coated with an unmodified phospholipid bilayer. Furthermore, the influence of Brij on the loading capacity and release behavior of a poorly water-soluble drug was assessed using quercetin as a model drug. Biocompatibility assessments demonstrated that MLB exhibited low cytotoxicity when tested on HeLa cells, indicating its potential for biomedical applications.