A novel series of sulfur-containing analogs derived from the 3-hydroxy-6-methyl-2-((4-phenylpiperazin-1-yl)methyl)-4H-pyran scaffold was synthesized. Spectroscopic techniques and elemental analysis confirmed their structures. The biological potential of these compounds, along with their previously reported bioisosteres, was assessed as tyrosinase inhibitors, as well as antitubercular and antidermatophytic agents. In all derivatives where the carbonyl group is converted to a thiocarbonyl group, tyrosinase inhibition increases significantly, with the most effective compounds being identified as compounds 6c and 6d, which carry the 4-fluoro and 4-nitro groups, with IC50 values of 0.143 and 0.121 mg/mL, respectively, compared with kojic acid (0.067 mg/mL). Molecular modeling predicted enhanced engagement with the copper ions in tyrosinase active site upon shifting from carbonyl to thiocarbonyl. Similarly, all thioxo-based analogs (6a–d) demonstrated antimycobacterial activity comparable to that of the reference drug ethambutol, particularly against Mycobacterium avium. These compounds also showed pronounced antidermatophytic activity, with MIC values ranging from 1 to 2 μg/mL against Trichophyton mentagrophytes var. erinacei, Epidermophyton floccosum, and Microsporum gypseum. Cytotoxicity assays in HeLa and MRC-5 cell lines revealed that the compounds remained bioactive at non-toxic concentrations ( ≥ 128 μg/mL). Overall, the replacement of the carbonyl group with a thioxo functionality markedly enhanced the bioactivity of the derivatives predictably through improved tyrosinase inhibition, highlighting their potential as promising lead scaffolds for the future development of multifunctional therapeutic agents.
Huntington's disease (HD) is a progressive neurodegenerative disorder with a poorly understood neurobiological basis. Among the various forms of programmed cell death implicated in neurodegeneration, necroptosis has recently garnered significant attention. Notably, dysregulated necroptosis provokes immune response that drives excessive pro-inflammatory cytokine production, promoting further necroptotic cell death through TNF-α/RIPK1 signaling. Consequently, necroptosis exacerbates neuroinflammation, contributing to the progression of different neurodegenerative diseases. However, the precise role of necroptosis in HD pathogenesis remains unclear. Given the growing interest in repurposing FDA-approved drugs for novel therapeutic interventions, this study investigates the anti-cancer agent Pazopanib (Pazo) as a potential neuroprotective approach for HD. This study assesses Pazo's ability to mitigate necroptosis by targeting the RIPK1/RIPK3/MLKL pathway in a model of HD produced by 3-nitropropionic acid (3-NP). Sixty male Wistar rats were randomly assigned to four groups: Group I received normal saline; Group II received Pazo (15 mg/kg, i.p.); Group III received 3-NP (10 mg/kg, i.p.); and Group IV received 3-NP (10 mg/kg, i.p.) and Pazo (15 mg/kg, i.p.). Behavioral assessments, including open field, rotarod, and wire hanging tests, demonstrated that Pazo significantly improved motor function. At the molecular level, Pazo inhibited PGAM5, a key regulator of mitochondrial fission, effectively reversing the RIPK1/RIPK3/MLKL necroptotic cascade and the consequent immune activation. This suppression of necroptosis was associated with reduced microgliosis, neuroinflammation and enhanced neuronal survival within the striatum. These findings highlight the potential of Pazo as a neuroprotective agent against HD by leveraging its antioxidant, anti-inflammatory, immune-modulating, and anti-necroptotic properties.
Mitochondrial dysfunction is a hallmark of chronic obstructive pulmonary disease (COPD). Nevertheless, the precise molecular mechanisms of COPD have yet to be fully elucidated. Protein−protein interaction (PPI) network construction and weighted gene co-expression network analysis (WGCNA) were conducted to identify hub genes related to mitochondrial homeostasis. A TNF receptor superfamily member 17 (TNFRSF17)-knockdown model was established in human bronchial epithelial (HBE) cells treated with cigarette smoke extract (CSE), and in mice exposed to CS and lipopolysaccharide (LPS). Cell counting kit-8, enzyme-linked immunosorbent assay, flow cytometry, JC-1 staining, senescence-associated β-galactosidase staining, western blot analysis, and hematoxylin−eosin staining were used to evaluate cellular function, inflammation, and pathology. The involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was investigated using colivelin analog 1 (C-A1). CD19, POU2AF1, FCRLA, and TNFRSF17 were identified as mitochondrial homeostasis-related hub genes, all of which were upregulated in COPD. Following TNFRSF17 knockdown, COPD mice exhibited reduced alveolar destruction, inflammatory cell infiltration, and collagen deposition. TNFRSF17 knockdown alleviated CS-induced mitochondrial membrane depolarization, calcium overload, reactive oxygen species (ROS) accumulation, ATP depletion, IL-6 and TNF-α secretion, and cellular senescence both in vitro and in vivo. TNFRSF17 knockdown suppressed the phosphorylation of JAK2 and STAT3. The protective effects mediated by TNFRSF17 knockdown were significantly abrogated by the C-A1 treatment. TNFRSF17 knockdown inhibits mitochondrial dysfunction, inflammation, and senescence in COPD by obstructing the JAK2/STAT3 pathway, offering a promising therapeutic strategy for COPD.
Inhibiting the malignant proliferation is crucial for managing the cancer progression. NCAPG (Non-SMC condensin I complex subunit G) is a main component in cell proliferation, which is highly expressed in liver tumors and negatively correlated with the overall survival of hepatocellular carcinoma (HCC) patients. In this study, we identified bufalin as a molecular glue for the first time that specifically degraded NCAPG by coupling it to cathepsin V (CTSV). Distinguished from traditional PROTACs, bufalin served as a molecular glue with the distinct advantages of a smaller molecular weight and superior bioavailability. This degradation inhibited the proliferation of HCC cells by inducing G2/M phase cell cycle arrest at low doses (20–40 nM), but did not trigger the apoptosis signaling. Using co-immunoprecipitation and confocal microscopy, we confirmed the interaction between CTSV and NCAPG by bufalin. Knockdown of CTSV or NCAPG attenuated the anti-proliferation effects of bufalin in HCC cells. Cell cycle analysis also showed significantly reduced G2/M arrest in knockdown cells. The downstream proliferation regulators Cyclin D1 and CDK1 were also regulated by bufalin in a CTSV/NCAPG-dependent manner. Our study not only identified the CTSV-NCAPG complex as a novel therapeutic target but also discovered a potential molecular glue, bufalin, which exerts anti-proliferation effects through cell cycle regulation. These findings highlight the potential clinical translational value of bufalin as a promising, bioavailable therapeutic agent for the targeted treatment of liver cancer.
Breast cancer remains one of the leading causes of mortality among women worldwide, and triple-negative breast cancer continues to show poor clinical outcomes due to the absence of actionable targets. As platinum-based therapies face well-recognized limitations related to toxicity, resistance, and restricted mechanisms of action, manganese (Mn) complexes have recently attracted interest as non-platinum metallodrugs with multimodal antitumor activity, including DNA interaction, Fenton-like ROS generation, and immunomodulation such as activation of the cGAS–STING pathway. This narrative review summarizes studies identified through PubMed and Web of Science searches up to April 2025 and integrates current progress on Mn complexes in breast cancer, including their cytotoxic effects, immune-related functions, and emerging theranostic applications. Representative complexes are compared in terms of structure, activity, and early structure–activity features. At the same time, key translational challenges—including solubility, kinetic and redox stability, bioavailability, and Mn-specific toxicity such as neurotoxicity—are highlighted alongside the limited pharmacokinetic and safety data currently available. Overall, this review outlines both the therapeutic potential and the practical limitations of Mn complexes and identifies research priorities needed to advance these agents toward meaningful clinical translation in breast cancer.
Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting other signaling pathways may be helpful in the management of AD. Particularly, preprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator protein of low-density lipoprotein (LDL), is intricate in the pathogenesis of AD. Normally expressed PCSK9 in the brain plays a critical role in the regulation of neuronal differentiation and apoptosis, and degradation of LDL receptors (LDLRs). However, exaggerated brain PCSK9 via induction of inflammation and oxidative stress and related neurodegeneration may induce AD development. Therefore, neuronal PCSK9 has dual role in the CNS. Nevertheless, the exact role of PCSK9 in AD neuropathology is still elusive. Therefore, in the review, we try to revise and discuss the potential role of PCSK9 in the pathogenesis of AD, and how targeting of this protein may be helpful in the management of AD.
Despite the fact that meta-analysis is a widely utilized methodology in synthesis of evidence from clinical trials, traditional methodologies have limitations with regards to informing dose selection, time-course dynamics and quantitative decision-making across the drug-development continuum. To overcome these limitations, a complex evidence-synthesis model, Model-Based Meta-analysis (MBMA) was proposed to combine pharmacometric modeling and the concepts of meta-analysis. MBMA provides predictive information, by explicitly considering dose-response relationships and longitudinal treatment effects, and by considering between-study heterogeneity, that goes beyond the information provided by a single-time-point summary. Although proven valuable, MBMA remains underutilized and inconsistently applied, partly due to methodological complexity, lack of standardization, and a continued misunderstanding with traditional meta-analysis. The aim of the present review is to critically assess MBMA as a quantitative engine of model-informed drug development (MIDD) and demystify the methodological underpinnings of this technique and its practical applicability. The major MBMA techniques are summarized and synthesized, namely nonlinear mixed-effects modelling, Bayesian hierarchical models and the estimation of models and validation as well as the quantification of uncertainty. The use in therapeutic areas is discussed to demonstrate how MBMA can be used in dose optimization, comparison of efficacy, paediatric extrapolation, and trial design. Regulatory considerations and emerging guidance supporting model-based approaches are also addressed. Landmarking MBMA as a significant distinction from traditional meta-analysis and highlighting its influence on clinical and regulatory decision-making, the review establishes MBMA as an undeniably imperative instrument in translating the heterogeneous clinical data into actionable insights across the lifecycle of drug-development.
Mediated by their protein transduction domain, cell-penetrating peptides (CPPs) have been widely explored for facilitating intracellular delivery of drugs and small molecules. In this study, a radiolabeled, 2-nitroimidazole conjugated TAT (TAT - transactivator of transcription) peptide was prepared and evaluated for targeting tumor hypoxia. The conjugate was radiolabeled with iodine-125 and comprehensive in vitro and in vivo evaluations were conducted to assess its potential to target hypoxic cells. A radiolabeled [125I]I-TAT was also prepared as a control. In vitro studies carried out in CHO cells under hypoxic conditions revealed three fold uptake of [125I]I-TAT-2-NIM compared to [125I]I-TAT at 1 h post-incubation, which further increased sixfold at 4 h post-incubation, clearly demonstrating the role of nitroimidazole in targeting hypoxic cells. However, the study also revealed a negative influence of hypoxia in cellular uptake, wherein the radiolabeled TAT peptides showed a lower uptake in cells under hypoxic conditions than in normoxic conditions. In vivo, [125I]I-TAT-2-NIM showed uptake and retention in the tumor with the tumor/muscle ratio above 2 at all time points studied. However, the tumor/blood ratio was found to decrease with time. Though [125I]I-TAT-2-NIM showed higher accumulation in hypoxic cells compared to [125I]I-TAT in vitro, the negative influence of hypoxia on the cellular uptake of TAT-peptides possibly indicates their limitation for hypoxia targeting applications.
Lung cancer remains a leading cause of cancer-related mortality, and resistance to platinum-based chemotherapy necessitates the development of alternative metal-based therapeutics. In this study, two iridium(III) complexes were synthesized and systematically investigated for their photophysical and biological properties. Spectroscopic characterisation confirmed effective ligand coordination and metal-to-ligand charge transfer behaviour. Both complexes exhibited significant interaction with calf thymus DNA, with intrinsic binding constants of 5.01 × 104 M−1 and 1.08 × 104 M−1, and showed strong affinity towards human serum albumin (KHSA up to 8.30 × 106 M−1). Antioxidant activity assessed by the DPPH assay revealed moderate radical scavenging ability. Cytotoxicity studies using an MTT assay demonstrated concentration-dependent antiproliferative activity against A549 lung cancer cells, with IC50 values of 57.6 µM and 36.0 µM, while maintaining low toxicity towards normal HEK 293 cells.
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