ABSTRACT
Continued interest in the bioactive alkaloids led to the isolation of five undescribed alkaloids (1-5), ophiorglucidines A-E, and seven known analogues (6-12) from the water-soluble fraction of Ophiorrhiza japonica. The structures were elucidated based on spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. The structure of 1 was characterized as a hexacyclic skeleton including a double bridge linking the indole and the monoterpene moieties, which is the first report of a single crystal with this type of structure. Moreover, the inhibitory effect of zwitterionic indole alkaloid glycosides on xanthine oxidase was found for the first time. The alkaloids 2 and 3, both of which have a pentacyclic zwitterionic system, were more active than the reference inhibitor, allopurinol (IC50 = 11.1 µM) with IC50 values of 1.0 µM, and 2.5 µM, respectively. Structure-activity relationships analyses confirmed that the carbonyl group at C-14 was a key functional group responsible for the inhibitory effects of these alkaloids.
Subject(s)
Enzyme Inhibitors , Indole Alkaloids , Monoterpenes , Rubiaceae , Xanthine Oxidase , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/metabolism , Rubiaceae/chemistry , Structure-Activity Relationship , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Indole Alkaloids/isolation & purification , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Monoterpenes/chemistry , Monoterpenes/pharmacology , Monoterpenes/isolation & purification , Molecular Structure , Dose-Response Relationship, Drug , Models, Molecular , Crystallography, X-RayABSTRACT
A series of oxygenated yohimbane alkaloids, including three new compounds, ophiorrhines H-J (1-3), and seven known compounds, were isolated from the aerial parts of Ophiorrhiza japonica. The structures with absolute configurations were elucidated by extensive MS and NMR spectroscopic methods, as well as the single crystal X-ray diffraction and ECD calculations. Ophiorrhines H (1) and I (2) represent key oxygenated intermediates in the formation of aromatic ring E in the demethoxycarbonyl-3,14-dihydrogambirtannine (10). Ophiorrhine J (3) is a highly oxidized yohimbane derivative with the planar superconjugated system. The cytotoxic activities of all alkaloids against five human cancer cell lines were evaluated.
Subject(s)
Alkaloids , Rubiaceae , Humans , Molecular Structure , Indole Alkaloids , Alkaloids/pharmacology , Alkaloids/chemistryABSTRACT
[This corrects the article DOI: 10.3389/fphar.2018.01525.].
ABSTRACT
ß-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial-mesenchymal transition (EMT) markers and AKT/GSK-3ß signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.
