Current topics in medicinal chemistry最新文献

Introduction: Dihydromyricetin (DMY) presents itself as a promising therapeutic candidate due to its inhibitory effects on various receptor tyrosine kinases, prompting an investigation of its structural characteristics, molecular interactions, and biological activity across the FGFR, HER, PDGFR, and VEGFR families.

Methods: Protein sequences and structures for FGFR1/2, HER2/3, PDGFRA/B, and VEGFR1/2 were retrieved from UniProt/PDB. DMY and reference inhibitors were docked to each kinase using AutoDock Vina. Anti-angiogenic activity was measured by HET-CAM assay with vessel metrics quantified via IKOSA CAM. MTT determined cytotoxicity (IC₅₀) and tumor-selectivity index in 4T1 and L929 cells; data (mean ± SEM) were analyzed by one-way ANOVA with Tukey's test (p < 0.005).

Results: DMY exhibited docking scores comparable to established inhibitors, achieved over 45 % inhibition of neovascularization in the HET-CAM assay at nanomolar concentrations, displayed a tumor-selectivity index of less than one in 4T1 versus L929 cells (mirroring many clinical chemotherapeutics), and, notably, coadministration with doxorubicin reduced in vitro cardiotoxicity markers.

Discussion: The high-affinity, multi-kinase binding profile and significant anti-angiogenic efficacy underscore DMY's multifunctional potential, while its tumor-selectivity index aligns with accepted therapeutic risk-benefit balances and its cardioprotective effect suggests a way to mitigate anthracycline toxicity.

Conclusion: These findings indicate that DMY is a multifunctional agent exhibiting both antiangiogenic and cytotoxic properties, warranting further preclinical and clinical investigation.

Betanin is widely consumed around the globe either as beetroot directly or as one of the key ingredients in food and pharmaceutical preparations. The health benefits of Betanin, including the treatment of numerous neurological diseases and brain cancer, have been reported extensively. Betanin has gained global attention due to notable anti-inflammatory, antioxidant, and anti-cancer activities. Recently, there has been growing attention on the usage of Betanin to prevent or delay the onset of neurodegenerative disorders. This review recapitulates available information from various recent pre-clinical studies on Betanin in several neurological diseases, such as Parkinson's disease, Alzheimer's disease, aging, brain stroke, anxiety, and neuropathic pain. Betanin exhibits remarkable neuroprotective effects via activation of the Nrf2 signaling pathway, inhibition of the production and expression of pro-inflammatory mediators and reactive oxygen species, along with suppression of the NF-κB signaling pathway. Taking betanin as part of a healthy diet may aid in the management of various brain-related disorders. This review focuses on the neurological conditions for which betanin has shown therapeutic potential, highlighting its beneficial properties, cellular and molecular mechanisms of action, and its relevance in light of current research. Based on the available evidence, betanin could be considered a promising candidate and lead compound in the drug development process for the prevention, treatment, and management of several neurological disorders in the future.

Neurodegenerative disorders (NDDs) are a major global health concern and the fifth leading cause of death worldwide. Huntington's disease (HD) is an NDD regarded as a rare, genetic, and advanced disease that occurs due to the duplication of cytosine, adenine, and guanine (CAG) trinucleotide repeats on chromosome 4p, located in the Huntingtin gene (HTT). There is no specific therapy available for HD. This review examines current evidence on various nutraceuticals as therapeutic or preventive agents in HD and their benefits in protecting against neuronal damage, oxidative stress, mitochondrial dysfunction, and combating excitotoxicity and neuroinflammation. Moreover, the beneficial role of nutraceuticals in HD involves averting defective energy metabolism, protein misfolding and aggregation, and epigenetic modulation, as well as strengthening cognitive and behavioral health. Nutraceuticals are naturally derived, bioactive components generally available in foods, dietary supplements, and herbal products, and they contribute to health promotion and disease prevention. These nutraceuticals possess potent antioxidant, anti-inflammatory, and neuroprotective properties, which help minimize the risk of HD. Moreover, antibacterial, antiviral, antimicrobial, anticancer, antiaging, antidiabetic, antihyperlipidemic, and immunobooster characteristics attract a large population worldwide. The wide availability of nutraceuticals in fruits, vegetables, and several naturally occurring foodstuffs supports their accessibility. These nutraceuticals function by stabilizing mitochondrial function, counteracting calcium overload, minimizing oxidative stress, and preventing inflammatory responses, among other mechanisms. The wide acceptance and demand for these nutraceuticals are due to their multifunctional role, economic benefits, and safety profile. The most promising nutraceuticals in the prevention and therapy of HD discussed are Curcumin, Resveratrol, Quercetin, Epigallocatechin Gallate, Hesperidin, Coenzyme Q10, Kaempferol, Silymarin, Astaxanthin, Lycopene, and Rosmarinic acid.

Diabetes is a long-term metabolic disorder characterized by elevated blood glucose levels and is primarily classified into Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM). Conventional drug delivery systems often face limitations such as low bioavailability, inadequate target specificity, and the need for frequent dosing. Drug targeting offers significant advantages in diabetes treatment by enhancing therapeutic efficacy and reducing side effects. This is achieved by binding drug-loaded carriers to specific receptors on insulin-sensitive tissues or pancreatic β-cells, ensuring precise action at the disease site and improving patient compliance. Several therapeutic targets have been identified to improve glycemic control and overcome the limitations associated with traditional drug delivery approaches. The present study provides insights into emerging targets for diabetes management, including AMPK (AMP-Activated Protein Kinase), glucose absorption inhibitors, renal glucose reabsorption inhibitors, GLP-1 (Glucagon- Like Peptide-1) agonists, SGLT2 (Sodium-Glucose Cotransporter-2) inhibitors, and PPAR-γ (Peroxisome Proliferator-Activated Receptor Gamma) modulators. Increasing attention is also being given to multi-targeted therapy, which simultaneously modulates multiple interconnected physiological pathways involved in diabetes pathogenesis. Such strategies have demonstrated the potential to improve glycemic control, reduce long-term complications, and offer better safety profiles compared to monotherapy. Given the multifactorial nature of diabetes, a combination of precisionbased and multi-targeted approaches holds promise for developing safer, better tolerated, and patient- centered antidiabetic therapies. This review highlights recent advances in identifying novel therapeutic targets and drug delivery strategies, contributing to the evolving paradigms that may shape the future of diabetes care.

Alstonia boonei (Apocynaceae) is a medicinal plant widely used in West and Central Africa to manage malaria, fever, intestinal worms, rheumatism, and hypertension. This review compiles evidence on its traditional uses, phytoconstituents, pharmacological activities, and formulations, to encourage future research into its therapeutic potential for modern health challenges. Literature review confirms notable anti-inflammatory, antimalarial, and ulcer-protective activities, while additional studies highlight its potential in antioxidant, anti-diabetic, neuroprotective, antiobesity, cytochrome P450 (CYP) enzyme inhibitory, anti-cataract, anticancer, and antibacterial effects. Phytochemical analysis reveals the presence of diverse bioactive compounds, including alkaloids, saponins, tannins, terpenes, phenolic compounds, and glycosides, which may act individually or synergistically to yield broad pharmacological actions. Recent experimental data reinforce its therapeutic relevance, positioning Alstonia boonei as a promising source of natural products. The wide spectrum of biological activities, coupled with the structural diversity of its phytoconstituents, underscores its importance as a valuable medicinal resource. In conclusion, Alstonia boonei shows significant potential for the development of anti-inflammatory, antimalarial, and ulcerprotective bioactive agents, justifying further scientific exploration and drug discovery efforts.

Introduction: Primary Sclerosing Cholangitis (PSC) remains a significant challenge in hepatology with an unclear pathogenesis and limited treatment options. This study employed Mendelian Randomization (MR) to explore novel pathogenic mechanisms of PSC.

Methods: We analyzed publicly available datasets, including cis-eQTL, cis-pQTL, 731 immune cell profiles, DNA methylation data, and PSC GWAS summary statistics. Using Inverse Variance Weighted (IVW) as our primary method, we identified genes causally associated with PSC. Subsequent mediation analyses elucidated how DNA methylation regulates gene expression and how these genes influence PSC through specific immune cell subpopulations.

Results: Our analysis revealed a significant protective effect of BTN3A2 expression against PSC risk (IVW OR 0.838, 95% CI 0.792-0.887, P = 1.12E-09). Mediation analysis indicated that methylation at cg23465465 had a largely mediated effect on PSC risk through BTN3A2 regulation (89.3% mediated effect). Additionally, BTN3A2 exerted partial protection via CD14+CD16+ monocytes (4.7% mediation).

Discussion: This study suggests a protective role for BTN3A2 in PSC pathogenesis, supported by reliable DNA methylation regulation. Although CD14+CD16+ monocytes had a minor impact, they provide new insights into the immune mechanisms of PSC. However, these findings require cautious interpretation pending experimental validation.

Conclusion: These findings identify BTN3A2 as a causal protective factor in PSC, mediated by DNA methylation and CD14+CD16+ monocyte-driven immunity, highlighting its therapeutic potential for precision medicine.

Fungal infections now cause approximately 3.75 million deaths annually, nearly double previous estimates, and account for about 6.8% of all global deaths, surpassing those from tuberculosis and malaria combined. Fungal infections have become a greater worldwide health concern due to the emergence of drug-resistant forms, especially in immunocompromised people. Common drawbacks of conventional antifungal therapies include toxicity, low absorption, and resistance development. Low solubility, instability, and non-specific targeting are some of the reasons why conventional antifungal medicines usually show limited activity, resulting in less-than-ideal therapeutic outcomes and unfavorable side effects. A viable substitute is provided by combining nanotechnology with herbal medicine. Strong antifungal activities are found in natural bioactive chemicals found in herbal extracts. Encapsulated in nanocarriers, including metallic nanoparticles, liposomes, nanoemulsions, micelles, and ethosomes, these drugs exhibit improved solubility, stability, and targeted administration, which enhances therapeutic efficacy and decreases toxicity. According to studies, essential oils and polyphenolic chemicals work in concert to prevent fungal infections when they are encapsulated in nanocarriers. For example, fungal biofilms have been successfully penetrated by liposomal and transferosomal systems, which have been successful in getting beyond resistance mechanisms. Long-term drug release is made possible by lipid-based carriers and polymeric nanoparticles, which reduce side effects and improve patient compliance. To achieve the full potential of herbal-based nanoformulations in antifungal medication, future studies should concentrate on improving stability, refining formulation methods, and carrying out extensive clinical trials to confirm safety and efficacy. There is great potential for creating safer and more efficient medicines to fight multidrug-resistant fungal infections with this novel technique.

Background: Strokes represent a significant global health concern, with ischemic stroke being the most prevalent and deadly form. The pathogenesis of ischemic stroke involves complex mechanisms, including excitotoxicity, oxidative stress, and cell death. This study presents a computational design of novel GluN2B-selective N-Methyl-D-Aspartate receptor antagonists with potential therapeutic applications in neurodegenerative disorders.

Methods: 3D-Quantitative Structure-Activity Relationship (QSAR) model and molecular dynamics simulations were employed to design novel NMDA receptor antagonists. A dataset of 53 derivatives was analyzed using structure-based virtual screening, molecular docking, and pharmacophore modeling.

Results: Molecular docking and dynamics simulations confirmed the binding affinity and dynamic behavior of the designed compounds, providing insights into their potential as therapeutic agents. We identified lead compound 75 with high predicted affinity and selectivity for GluN2Bcontaining receptors. Drug-likeness assessment, synthetic accessibility evaluation, and molecular dynamics simulations confirmed favorable pharmacokinetic properties and target engagement stability.

Conclusion: These findings provide a rational framework for the development of selective NMDA receptor antagonists with improved safety and efficacy profiles.

Liver cancer is a highly aggressive malignancy, and bone metastasis is a severe complication that negatively affects prognosis and quality of life. However, the molecular mechanisms underlying liver cancer bone metastasis remain poorly understood. This review examined recent advances related to epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs), and liver cancer stem cells (LCSCs), with a focus on surface markers, interactions within bone marrow (BM) niche, and relevant signaling pathways. Liver cancer bone metastasis is driven by EMT activation, CTC dissemination, and LCSC colonization in BM niches. Surface markers such as CD133, CD44, CD90, CD13, EpCAM, and OV6 contribute to tumor heterogeneity, dormancy, and therapy resistance. Key processes such as BM homing, osteolysis, and immune suppression are regulated through the osteoblast-osteoclast-cancer stem cell (OB-OC-CSC) axis and CXCL12-CXCR4 signaling. Dormancy-regulating molecules, including Annexin II, GAS6, osteopontin, TSP-1, tenascin C, and fibronectin, further determine CSCs' quiescence or reactivation. These insights highlighted the complexity of liver cancer bone metastasis, and suggested potential therapeutic strategies targeting EMT, LCSCs, and OB-OC-CSC crosstalk. Future studies are encouraged to validate marker functions in clinical cohorts, elucidate dormancy-exit mechanisms, and explore immunomodulatory interventions to overcome microenvironment-mediated resistance.