Biflavone Ginkgetin,a Novel Wnt Inhibitor,Suppresses the Growth of Medulloblastoma

Medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefore,Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer.In our present study,we undertook a screening for antagonists of Wnt signaling from 600 natural compounds,and identified Ginkgetin,a biflavone isolated from Cephalotaxus fortunei var.alpina.Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 lM and structure–activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group.Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells.Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells.Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes,including Axin2,cyclinD1 and survivin in MB cells.The phosphorylation level of b-catenin also decreased in a time-and concentration-dependent manner.Collectively,our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling,and as such warrants further exploration as a promising antimedulloblastoma candidate.

Four new indole alkaloids from Plantago asiatica

Four new indole alkaloids,plasiaticines A-D(1-4),together with two known ones,were isolated from the seeds of Plantago asiatica.The structures of the new compounds were elucidated on the basis of comprehensive analysis of spectroscopic data.All compounds were tested for their cytotoxic activity,and all compounds except 4 were tested for their acetylcholinesterase(AChE)inhibitory activities.

Two Natural ent-kauranoids as Novel Wnt Signaling Inhibitors

Constitutively active Wnt signaling frequently occurs in most colon cancers.Therefore,inhibitors of Wnt signaling pathway could provide rational therapeutic effects for colorectal malignancy.Within this paper,we identified two inhibitors of Wnt signaling pathway,rabdoternin B and maoecrystal I from a natural ent-kauranoid library by a dualluciferase reporter gene assay.The two compounds inhibited Wnt signaling pathway in a concentration-dependent manner and exhibited selective cytotoxicity toward a number of colon carcinoma cell lines SW480,HCT116,and HT29,with only weak cytotoxicity towards the normal colonic epithelial cell line CCD-841-CoN.Rabdoternin B and maoecrystal I treatment induced G2/M phase arrest efficiently in SW480 cells as revealed by flow cytometry analysis.A further study found that maoecrystal I decreased the expression of Wnt signaling target genes,including c-myc,cyclin D1,survivin and Axin2 in colon cancer cells.Collectively our data suggests that rabdoternin B and maoecrystal I are novel inhibitors of canonical Wnt signaling pathway and may possess potentials for colon cancer therapy.

Cycloartane Glycosides from the Roots of Cimicifuga foetida with Wnt Signaling Pathway Inhibitory Activity

Four new 9,19-cycloartane triterpenoids,cimilactone E(1),cimilactone F(2),20-O-(E)-butenoyl-23-epi-26-deoxyactein(3),and 20,12b-O-diacetylcimiracemonol-3-O-b-D-xylopyranoside(4),together with four known constituents(5–8)were isolated from the roots of Cimicifuga foetida.The new structures were elucidated by extensive spectroscopic analysis.In addition,compounds 7 and 8 showed significant Wnt signaling pathway inhibitory activity,with IC50 values of 3.33 and 13.34 lM,respectively,using the luciferase reporter gene assay.

Monoterpenoid indole alkaloids from Alstonia rostrata

Four new monoterpenoid indole alkaloids,alstrostines C-F together with thirteen known alkaloids were isolated from the leaves and twigs of Alstonia rostrata.All structures of new compounds were elucidated based on NMR,FTIR,UV,and MS spectroscopic data.Alstrostines C-E might originate from keto-enol tautomerism of preakummicine during biogenetic pathway of akummicine.

Five new mexicanolide type limonoids from Heynea trijuga

Five new mexicanolide-type limonoids,heytrijunolides A-E(1-5)were isolated from the branches and leaves of Heynea trijuga.The structures of these new compounds were elucidated on the basis of extensive spectroscopic analysis.Compound 3 showed weak cytotoxicity against HL-60,SMMC-7721 and A-549 human tumor cell lines with the IC50 values of 21.88,20.66 and 12.70μM,respectively.

Exploring of drug leads from diversity-oriented Michael-acceptor library derived from natural products

A potential strategy for drug lead identification and in-active natural products re-discovery is elaborated.Starting from fifteen structurally diverse natural products,a focused library featured by Michael acceptors is constructed with IBX mediated oxidation.Biological assay on five tumor cell lines indicates that four Michael acceptors,8a,11a,12a,14a,are with improved cytotoxicity(3-10 folds more potent than the parent compounds),which merit further investigations.Further thiol-sensitive assay of the active hit 8a revealed that it was an irreversible Michael acceptor.The results suggest that the strategy is not only effective and relatively high discovery rate(28%),but also resource saving.

Rauvotetraphyllines A-E, new indole alkaloids from Rauvolfia tetraphylla

Five new indole alkaloids rauvotetraphyllines A-E(1-5),together with eight known analogues,were isolated from the aerial parts of Rauvolfia tetraphylla.The structures were established by means of spectroscopic methods.