Limonoids with Wnt signal inhibitory activity isolated from the fruits of Azadirachta excelsa

Activity-guided isolation of the Azadirachta excelsa MeOH extract using TOP assay led to the isolation of one new (1) and seven known (2–8) limonoids. Compound 4 exhibited TCF/β-catenin transcription inhibitory activity. It showed selective cytotoxicity against HCT116 and AGS which have active Wnt s...

Full description

Saved in:
Bibliographic Details
Published in:Phytochemistry letters 2015-03, Vol.11, p.280-285
Main Authors: Fuentes, Rolly G., Toume, Kazufumi, Arai, Midori A., Sadhu, Samir K., Ahmed, Firoj, Ishibashi, Masami
Format: Article
Language:English
Subjects:
Adenomatous polyposis coli
Colorectal cancer
Limonoids
β-Catenin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Activity-guided isolation of the Azadirachta excelsa MeOH extract using TOP assay led to the isolation of one new (1) and seven known (2–8) limonoids. Compound 4 exhibited TCF/β-catenin transcription inhibitory activity. It showed selective cytotoxicity against HCT116 and AGS which have active Wnt signal. •We isolated one new (1) and seven known (2–8) limonoids by activity-guided approach.•Limonoids with a 14,15-epoxide group strongly inhibited the TCF/β-catenin transcription.•Compound 4 was selectively cytotoxic to Wnt-dependent AGS and HCT116 cancer cells. The Wnt signal regulates various biological processes, and its aberrant activation is associated with the development of diseases. Thus, inhibiting the Wnt signal provides a promising strategy to treat these diseases. Our cell-based luciferase assay system, which targets the Wnt signal (TOP assay), revealed that Azadirachta excelsa inhibited the Wnt signal. The activity-guided isolation of the MeOH fruit extract of A. excelsa provided one new (1) and seven known (2–8) limonoids. Their structures were elucidated based on their spectroscopic data, and their NMR data were compared with those in the literature. Compounds 3–6 potently inhibited the Wnt signal with IC50 values of 127nM, 300nM, 252nM, and 121nM, respectively. Compound 4 exhibited selective cytotoxicity against AGS and HCT116. Western blot analysis showed that 4 did not affect the level or localization of β-catenin, but downregulated the level of c-myc. Our results suggested that 4 may have inhibited the Wnt signal by affecting the components downstream of β-catenin.
ISSN:1874-3900
1876-7486
DOI:10.1016/j.phytol.2015.01.015