ABSTRACT
Three new acylphloroglucinols (1-3) and four known biosynthetically related analogs (4-7) were isolated from the ethanol extract of a brown alga Sargassum nigrifoloides. Structures for 1-7 were characterized via detailed spectroscopic analyses especially 2D NMR data. Screening of these compounds in Alzheimer's diseases-related bioassays revealed moderate inhibitory activities against two therapeutically important kinases, CDK5 and GSK3ß. A preliminary structure-activity relationship was also discussed.
Subject(s)
Phloroglucinol/analogs & derivatives , Phloroglucinol/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Sargassum/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Glycogen Synthase Kinase 3/antagonists & inhibitors , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Phloroglucinol/pharmacology , Protein Kinase Inhibitors/pharmacology , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Oxidative stress is involved in the onset and progression of many human diseases. Activators of the Keap1/Nrf2/ARE pathway effectively inhibit the progression of oxidative stress-induced diseases. Herein, a small library of diterpenoids was established by means of phytochemical isolation, and chemical modification on naturally occurring molecules. The diterpenoids were subjected to a NAD(P)H: quinone reductase (QR) assay to evaluate its potential inhibition against oxidative stress. Sixteen diterpenoids were found to be novel potential activators of Nrf2-mediated defensive response. Of which, an isopimarane-type diterpenoid, sphaeropsidin A (SA), was identified as a potent activator of the Keap1/Nrf2/ARE pathway, and displayed approximately 5-folds potency than that of sulforaphane (SF). SA activated Nrf2 and its downstream cytoprotective genes through enhancing the stabilization of Nrf2 in a process involving PI3K, PKC, and PERK, as well as potentially interrupting Nrf2-Keap1 protein-protein interaction. In addition, SA conferred protection against sodium arsenite [As(III)]- and cigarette smoke extract (CSE)-induced redox imbalance and cytotoxicity in human lung epithelial cells, as wells as inhibited metronidazole (MTZ)-induced oxidative insult in Tg (krt4: NTR-hKikGR)cy17 transgenic zebrafish and lipopolysaccharide (LPS)-induced oxidative damage in wild-type AB zebrafish. These results imply that SA is a lead compound for therapeutic agent against oxidative stress-induced diseases, and diterpenoid is a good resource for discovering drug candidates and leads of antioxidant therapy.
Subject(s)
Antioxidant Response Elements , Diterpenes/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Animals , Antioxidants/pharmacology , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Survival , Homeostasis , Liver Neoplasms/metabolism , Mice , Molecular Docking Simulation , Oxidation-Reduction , Oxygen/chemistry , Tobacco Smoke Pollution , ZebrafishABSTRACT
Two polyketides, stemonones A (1) and B (2) with new skeletons, were isolated from the roots of Stemona tuberosa. Their absolute structures were fully characterized by comprehensive spectroscopic analyses and comparison of experimental electronic circular dichroism (ECD) spectra with calculated ones. The plausible biosynthetic pathways for 1 and 2 were also proposed. Anti-inflammatory assay confirmed that the two compounds showed moderate inhibitory effects on ß-glucuronidase release in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor.
Subject(s)
Anti-Inflammatory Agents/chemistry , Polyketides/chemistry , Stemonaceae/chemistry , Animals , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Cells, Cultured , China , Glucuronidase/metabolism , Molecular Structure , Neutrophils/drug effects , Plant Roots/chemistry , Polyketides/isolation & purification , Polyketides/pharmacology , RatsABSTRACT
One new 9,10-seco-abietane derivative, crotontomentosin A (1), four new abietane-type diterpenoids, crotontomentosins B-E (2-5), one new ent-halimane-type diterpenoid, crotontomentosin F (6), along with five known diterpenoids (7-11) and one known sesquiterpenoid (12) were obtained from the twigs and leaves of Croton caudatus Geisel. var. tomentosus Hook. The structures of the compounds were established on the basis of extensive spectroscopic data. Compounds 1-4 and 11 exhibited moderate to weak inhibitory activity against the proliferation of the Hela, Hep G2, MDA-MB-231, or A549 cell lines selectively.