Daphnane-type diterpenoids from Stellera chamaejasme L. and their inhibitory activity against hepatocellular carcinoma cells.

Daphnane-type diterpenoids, which are scarce in nature, exhibit potent growth-inhibitory activities against various cancer cells. To identify more daphnane-type diterpenoids, the phytochemical components in the root extracts of Stellera chamaejasme L. were analysed in this study using the Global Natural Products Social platform and the MolNetEnhancer tool. Three undescribed 1α-alkyldaphnane-type diterpenoids (1-3; named stelleradaphnanes A-C) and 15 known analogues were isolated and characterised. The structures of these compounds were determined using ultraviolet and nuclear magnetic resonance spectroscopy. The stereo configurations of the compounds were determined using electronic circular dichroism. Next, the growth-inhibitory activities of isolated compounds against HepG2 and Hep3B cells were examined. Compound 3 exhibited potent growth-inhibitory activities against HepG2 and Hep3B cells with half-maximal inhibitory concentration values of 9.73 and 15.97 µM, respectively. Morphological and staining analyses suggested that compound 3 induced apoptosis in HepG2 and Hep3B cells.

Prenylated flavonoids with significant anti-hepatoma activity from Daphne giraldii and effects on Fibroblast Growth Factor Receptor 1 (FGFR1).

We report here the orchestration of molecular ion networking (MoIN) and a set of computational and informatics assisted structural elucidation approaches in the discovery of 23 new prenyl-flavonoids and 13 known molecules from Daphne giraldii Nitsche (Thymelaeaceae), some of which possess significant bioactivity against hepatoma carcinoma. Daphnegiratriprenylone A (DPTP-A) represents the class of polyprenyl-flavonoids possessing a triprenyl substitution, and was identified with the guidance of mass spectrometry and nuclear magnetic resonance combined with computational approaches. This approach illustrates a paradigm shift in the application of computational tools for the direct assignment of new natural product structures and it was demonstrated to be reliable compared to conventional 2D-NMR techniques. Seventeen compounds exhibited potent and selective activity against Hep3B cells (IC50 ranging from 0.42 to 7.08 µM). Tyrosine kinase FGFR1 has emerged as a potential target of polyprenyl-flavonoids by a reverse pharmacophore mapping approach. We validated that the prenyl-flavonoids effectively inhibit FGFR1 using the Mobility Shift Assay, Western blot and molecular dynamics simulations, and the results suggest significant potency of the compounds towards FGFR1. These findings provide a new chemical class with strong links to traditional medicines, possessing reasonable safety for developing potential therapeutic agents for FGFR1-related diseases.

Vibsane-type diterpenoids from Viburnum odoratissimum inhibit hepatocellular carcinoma cells via the PI3K/AKT pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with an elevated danger of metastasis and a short survival rate. Vibsane-type diterpenoids with novel structures possess marked antitumor activities against multiple cancer cells. However, the exact mechanism is poorly unclear. PURPOSE: To assess the antitumor mechanism of vibsane-type diterpenoids derived from Viburnum odoratissimum (V. odoratissimum) against HCC cells in vitro and in vivo. METHODS: The main constituents in the ethyl acetate extract of V. odoratissimum (EAVO) were identified by LC-MS/MS. The antiproliferative activity of EAVO in vitro was evaluated by MTT assays. Annexin V-FITC/PI, AO/EB, and Hoechst 33,258 staining were employed to detect apoptosis. JC-1 fluorescence dye was used to detect the mitochondrial membrane potential (MMP). The levels of intracellular ROS and mitochondrial superoxides were assessed by H2DCF-DA and MitoSox staining, respectively. The levels of oxidative stress were determined by ROS Green™ H2O2 probe, hydroxyphenyl fluorescein (HPF), and the C11 BODIPY 581/591 fluorescent probe. Transcriptomics was performed to investigate the antitumor mechanism of EAVO in HCC. The molecular mechanism by which EAVO suppressed HCC cells was verified by Western blot, RT-PCR, and HTRF® KinEASE™-STK S3 kits. The efficacy and safety of EAVO in vivo were evaluated using Hep3B xenograft models. RESULTS: Vibsane-type diterpenoids were the main constituents of EAVO by LC-MS/MS. EAVO suppressed proliferation, aggravated oxidative stress, and promoted apoptosis in HCC cells. Moreover, EAVO dramatically inhibited tumor growth in Hep3B xenograft models. Transcriptomics results indicated that EAVO inhibited HCC cell proliferation by regulating the PI3K/AKT pathway. Vibsanin B, vibsanol I, and vibsanin S isolated from EAVO was used to further verify the antitumor activity of vibsane-type diterpenoids subsequently. Interestingly, the kinase results showed that vibsanin B and vibsanol I exhibited vital AKT kinase inhibitory activities. CONCLUSIONS: Collectively, this study provided a comprehensive mechanism overview of vibsane-type diterpenoids against HCC cells in vitro and in vivo. It also laid a foundation for further antitumor investigation of vibsane-type diterpenoids in V. odoratissimum.

Semi-synthesis and biological evaluation of flavone hybrids as multifunctional agents for the potential treatment of Alzheimer's disease.

7-O-galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer's disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced ß-amyloid (Aß) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of Aß aggregation (78.81% at 20 µM), potent AChE inhibitory potencies (IC50, 0.56 µM), and compound C4 presented the highest ability to inhibit BuChE (IC50, 5.77 µM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood-brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H2O2-induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.

Sesquineolignans derivatives with neuroprotective activity from the fruits of Crataegus pinnatifida.

Ten undescribed sesquineolignans (1-10), including four sesqui-norlignans (1-4), were isolated from the fruits of Crataegus pinnatifida. Their structures were determined by comprehensive spectroscopic analyses. All compounds were examined for their neuroprotective activities against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells. Among them, 6 and 8 showed comparable protective effect with 79.36% and 80.72% cell viability compared with the positive control Trolox (78.64%) at 25 µM.