Archiv der Pharmazie最新文献

Oxidative stress is responsible for the functional loss and sensory impairment of neurons, which leads to progressive loss of brain and spinal cord cells and contributes significantly to several neurological disorders, thus eventually resulting in brain atrophy and death. This study involves the isolation of lignans, including phyllanthin, hypophyllanthin, and nirtetraline, from Phyllanthus amarus. Furthermore, the phyllanhtin was semi-synthetically modified to give phyllanthin oxadiazole derivatives and was evaluated for neuroprotective activity in scopolamine-injured neuroblastoma-2a (N2A) cells. The biochemical assay for reactive oxygen generation (ROS) production in N2A cells was carried out using 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) dye, and the mitochondrial membrane potential (MMP) was determined in N2A cells by using JC-1 dye. Furthermore, the N2A neuronal deaths were evaluated using acridine orange (AO), ethidium bromide (EtBr), and propidium iodide dyes. Among them, nirtetraline, hypophyllanthin, phyllanthin, and compounds 21 and 31 showed potential neuroprotective effects in N2A cells against scopolamine-induced neurotoxicity by inhibiting ROS production and improving MMP. Moreover, the synthesized compounds were nontoxic to the N2A cell line. Furthermore, in silico docking studies predicted phyllanthin derivatives 21 and 31 exhibit neuroprotective activity by binding to the human NADPH-oxidase 5 enzyme. Thus, compounds 21 and 31 can be considered potential neuroprotective leads.

Ovarian cancer remains one of the most lethal gynecological malignancies, underscoring the need for novel therapeutic strategies. In this study, a series of pyrimidine-based nucleobase (7–14) and nucleoside (21–24) analogs were synthesized and evaluated for their potential anticancer activity through poly(ADP-ribose) polymerase (PARP) inhibition. These compounds were tested for in vitro cytotoxicity on ovarian cancer cell lines OVCAR-3 and KURAMOCHI. Among the synthesized derivatives—namely, 4-(4-substituted phenylamino)-1-cyclopentyl-5-(H/methyl)pyrimidine-2(1H)-ones (7–14) and 4-(4-substituted phenylamino)-1-(β-d-ribofuranosyl)-5-methylpyrimidine-2(1H)-ones (21–24)—compound 8 exhibited the most potent cytotoxic activity. It significantly reduced cell viability in OVCAR-3 (IC₅₀ = 27.1 ± 4.56 µM) and KURAMOCHI (IC₅₀ = 46.2 ± 4.87 µM) cells, outperforming the reference PARP inhibitor olaparib (IC₅₀ = 75.8 ± 6.1 µM for OVCAR-3, IC₅₀ = 84.5 ± 11.4 µM for KURAMOCHI). These results suggest that compound 8 is a promising lead candidate for further development as an anticancer agent targeting PARP in ovarian cancer.

Recent research has shown that heterocyclic compounds and their derivatives have garnered a great deal of attention in medicinal chemistry due to their noteworthy biological and pharmacological characteristics. A characteristic of both natural products and pharmaceutical drugs is the triazole nucleus which is one of the most significant heterocycles. Most pharmaceuticals include large amounts of heterocyclic nitrogen. One of the preferred structural motifs of triazoles, among nitrogen-containing heterocyclic compounds, has drawn a lot of interest from both academia and industry. Triazoles are widely used in organic synthesis, supramolecular chemistry, polymer chemistry, drug discovery, chemical biology, bioconjugation, fluorescence imaging, and materials research. Additionally, this intriguing heterocycle's many biological functions will be covered. Researchers, particularly those paying attention to the development of triazole derivatives with a number of synthetic methods—particularly the well-liked click chemistry approach—and their pharmacological outcomes such as antifungal, antitubercular, antibacterial, antiviral, and anticancer properties will find this review highly significant.

Mogroside V (MOG-V), a natural triterpene glycoside predominantly derived from the fruit pulp of Siraitia grosvenorii, is widely recognized as a high-intensity non-caloric sweetener. In recent years, it has attracted considerable research interest due to its broad pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and neuroprotective effects. Notably, MOG-V exhibits a remarkable capacity to scavenge intracellular reactive oxygen species (ROS), thereby supporting mitochondrial function and promoting cellular homeostasis. It has also shown promising efficacy in alleviating pneumonia. Mechanistic studies indicate that MOG-V modulates glucose and lipid metabolism through activation of the AMPK signaling pathway. Furthermore, it confers neuroprotective benefits in models of Parkinson's disease via regulation of critical metabolic pathways. Despite these advances, a comprehensive and critical outlook on the synthesis, pharmacological mechanisms, and therapeutic applications of MOG-V remains lacking. Based on the current research status and existing limitations, this review provides a comprehensive analysis of MOG-V, including its structural characteristics, novel synthetic approaches, and pharmacological investigations. Furthermore, it critically evaluates the therapeutic potential of MOG-V and identifies promising directions for future research. This study systematically consolidates and assesses the available knowledge of MOG-V, with the aim of clarifying its mechanistic foundations and proposing novel insights for subsequent studies.

The proto-oncogene c-KIT plays a key role in several cellular processes such as cell growth, survival, and proliferation. The overexpression of c-KIT has been implicated with the pathogenesis of several malignancies, such as gastrointestinal stromal tumors, acute myeloid leukemia (AML), mastocytosis, and melanoma. Mutation of c-KIT has been observed in acral, mucosal, and chronically sun-damaged melanoma subtypes marking it as a key therapeutic target for melanoma. Moreover, the increasing incidence and mortality rate associated with melanoma further marks the importance of developing new therapeutic modalities. Herein, the progress in the design, structure–activity relationship, mechanisms, and development of c-KIT small molecule inhibitors for melanoma is discussed with the aim of guiding future c-KIT-based melanoma therapeutics.

The antidiabetic efficacy of Elaeocarpus grandis, belonging to the Family Elaeocarpaceae, was investigated using the streptozotocin-induced hyperglycemia model. The ethyl acetate and petroleum ether fractions demonstrated a notable hypoglycemic impact in a rat model of type 2 diabetes mellitus (T2DM), compared to the negative control group. The chemical assessment of these fractions resulted in the isolation and identification of six known compounds (17–22). LC-HR-ESI-MS metabolomic profiling yielded the provisional identification of sixteen metabolites (1–16) across various chemical classes. In silico investigations, encompassing molecular docking and dynamics simulations, indicated that the compounds heterophylliin A (22), as well as habbemine A (12) and elaeocarpinoside (15), can interact with critical enzymes implicated in glucose metabolism, specifically dipeptidyl peptidase-IV and aldose reductase. Moreover, heterophylliin A (22) markedly decreased the expression of inflammatory markers (IL-1β, TNF-α, IL-6, and TGF-β) in diabetic rats. These findings prompt additional research on E. grandis, specifically its bioactive constituent heterophylliin A, which exhibits intriguing antidiabetic effects and warrants further exploration as a potential treatment agent for T2DM.

3-Deoxysappanchalcone (3-DSC), extracted from Caesalpinia sappan L., is recognized for its anti-inflammatory, anti-influenza, and anti-allergic effects, but its antithrombotic properties have not been investigated. This study explores whether 3-DSC exhibits antithrombotic effects and examines the mechanisms involved. The antithrombotic properties of 3-DSC were assessed through various methods, including tests for clotting times, platelet aggregation analysis, evaluation of factor Xa activity and production, nitric oxide levels, and the expression of related proteins. This study found that 3-DSC extended the clotting time in human platelet-poor plasma at levels comparable to rivaroxaban, a standard anticoagulant, and reduced platelet aggregation triggered by ADP or the thromboxane A2 analog U46619. Additionally, 3-DSC suppressed the phosphorylation of PLCγ2 and PKC, as well as intracellular calcium release, which are essential for platelet aggregation. It also decreased the expression of adhesion molecules P-selectin and PAC-1. Furthermore, 3-DSC promoted nitric oxide production while reducing endothelin-1 secretion in endothelial cells exposed to ADP or U46619. Lastly, it inhibited both the activity and production of coagulation factor Xa in endothelial cells and prevented activated factor X (FXa)-induced platelet aggregation. Injection of 3-DSC significantly shortened the time required for thrombus resolution, reduced the size and number of thrombi, and decreased mortality in mouse models of thromboembolism. The study demonstrates that 3-DSC effectively exhibits antithrombotic activity by prolonging the clotting time, inhibiting platelet aggregation, and reducing factor Xa activity, comparable to standard anticoagulants. These findings highlight the potential of 3-DSC as a promising therapeutic agent targeting multiple pathways involved in thrombosis, with reduced side effects.

The natural polyphenol resveratrol, found in several plants, has garnered significant interest due to its beneficial effects on health and for its potential anticancer properties. Studies have demonstrated that it can alter various signaling pathways linked to cancer development and that it inhibits tumor development and spread by exerting several antiproliferative, proapoptotic, anti-inflammatory, and antiangiogenic mechanisms. Its role in regulating oxidative stress and epigenetic modifications further enhances its therapeutic potential. Nevertheless, despite promising preclinical results, clinical translation is to some extent limited by bioavailability, metabolism, and dosage. This updated review explores the mechanisms, also from a structural point of view, behind the anticancer properties of resveratrol, focusing on its impact on crucial signaling networks in different cancer models. Additionally, it overviews the current limitations of resveratrol-based treatments and suggests potential improvements through innovative delivery methods, drug combination approaches, and development of new derivatives. This review was conceived as an update with respect to contributions already present in the literature, thus particular attention has been dedicated to the contribution reported in the literature within the last 5 years and to these studies reporting in vivo data.