ABSTRACT
A series of novel hybrid compounds were designed, synthesized, and utilized as multi-target drugs to treat Alzheimer's disease (AD) by connecting capsaicin and tacrine moieties. The biological assays indicated that most of these compounds demonstrated strong inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities with IC50 values in the nanomolar, as well as good blood-brain barrier permeability. Among the synthesized hybrids, compound 5s displayed the most balanced inhibitory effect on hAChE (IC50 = 69.8 nM) and hBuChE (IC50 = 68.0 nM), and exhibited promising inhibitory activity against ß-secretase-1 (BACE-1) (IC50 = 3.6 µM). Combining inhibition kinetics and molecular model analysis, compound 5s was shown to be a mixed inhibitor affecting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. Additionally, compound 5s showed low toxicity in PC12 and BV2 cell assays. Moreover, compound 5s demonstrated good tolerance at the dose of up to 2500 mg/kg and exhibited no hepatotoxicity at the dose of 3 mg/kg in mice, and it could effectively improve memory ability in mice. Taken together, these findings suggest that compound 5s is a promising and effective multi-target agent for the potential treatment of AD.
Subject(s)
Alzheimer Disease , Tacrine , Mice , Animals , Tacrine/chemistry , Alzheimer Disease/drug therapy , Capsaicin/pharmacology , Capsaicin/therapeutic use , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/metabolism , Amyloid beta-Peptides , Molecular Docking Simulation , Drug Design , Structure-Activity RelationshipABSTRACT
A new bergamotane-type sesquiterpene, named axanthiol A (1), and six known compounds (2-7) were isolated from the rhizomes of Amomum villosum var. xanthioides. Their structures were established on the basis of extensive spectroscopic analysis and the absolute configuration of 1 was confirmed by the Mosher ester method. Moreover, all the isolates were evaluated for their effects on LPS-induced nitric oxide (NO) production, and compound 5 showed efficacious inhibitory activity with IC50 value of 34.81 µM.
Subject(s)
Amomum/chemistry , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Animals , Drug Evaluation, Preclinical , Lipopolysaccharides/pharmacology , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Nitric Oxide/metabolism , RAW 264.7 Cells , Rhizome/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
PURPOSE: Polyphyllin VI, a main active saponin isolated from traditional medicinal plant Paris polyphylla, has exhibited antitumor activities in several cancer cell lines. In the present study, we investigated the antitumor effect of Polyphyllin VI against human osteosarcoma cells (U2OS) and the underlying molecular mechanisms. METHODS: The U2OS cell lines were used to determine the antiproliferative effect of Polyphyllin VI by CCK8 assay. Cell cycle was analyzed by flow cytometry. The Polyphyllin VI-induced apoptosis was determined by Annexin V-APC/7-AAD apoptosis detection kit and JC-1 staining. Meanwhile, the autophagy was determined by acridine orange staining. The apoptosis and autophagy-related proteins were monitored by Western blot assay. Subsequently, intracellular hydrogen peroxide (H2O2) and the activation of ROS/JNK pathway were detected. RESULTS: Polyphyllin VI could potently inhibit cell proliferation by causing G2/M phase arrest. Polyphyllin VI induced mitochondria-mediated apoptosis with the upregulation of proapoptotic proteins Bax and poly ADP-ribose polymerase, and downregulation of antiapoptotic protein Bcl-2 in U2OS cells. Concomitantly, Polyphyllin VI provoked autophagy with the upregulation of critical Atg proteins and accumulation of LC3B-II. Intracellular H2O2 production was triggered upon exposure to Polyphyllin VI, which could be blocked by ROS scavenger. Polyphyllin VI dramatically promoted JNK phosphorylation, whereas it decreased the levels of phospho-p38 and ERK. CONCLUSION: Our results reveal that Polyphyllin VI may effectively induce apoptosis and autophagy to suppress cell growth via ROS/JNK activation in U2OS cells, suggesting that Polyphyllin VI is a potential drug candidate for the treatment of osteosarcomas.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Bone Neoplasms/drug therapy , Osteosarcoma/drug therapy , Apoptosis/drug effects , Autophagy/drug effects , Bone Neoplasms/pathology , Cell Line, Tumor , Humans , Hydrogen Peroxide/metabolism , MAP Kinase Signaling System/drug effects , Mitochondria/metabolism , Osteosarcoma/pathology , Reactive Oxygen Species/metabolismABSTRACT
Objective: To identify the chemical components in traditional Chinese herbal medicine Ginseng by high performance liquid chromatography diode array detector (HPLC-DAD) and High performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS). Methods: An Agilent Zorbax XDB-C18 column (250 mm X 4.6 mm, 5 μm) was used for isolation and identification of chemical components in Ginseng with a mobile phase of acetonitrile and water in gradient elution. A gradient program was used as follows: 1-35 min, 19% A; 35-55 min, 19%-29% A; 55-70 min, 29% A; 70-110 min, 29%-40% A; 110-150 min, 95% A. The flow rate was set at 1.0 ml/min, the injection volume was 20 μl, the column temperature was set at 20°C. The time-of-flight mass spectrometer was equipped with an EIS ion source. Scanning mass range was between m/z 100-1 350. Results: Thirty-nine chemical compounds in Ginseng were identified unequivocally. Conclusion: Chromatographic demonstration of 39 chemical compounds of Ginseng in one run is achieved by HPLC-TOF/MS, which provides a foundation for further study on the metabolism and action mechanism of traditional Chinese herbal medicine.