UM
Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer
Chan D.S.-H.1; Yang H.1; Kwan M.H.-T.1; Cheng Z.1; Lee P.1; Bai L.-P.1; Jiang Z.-H.1; Wong C.-Y.2; Fong W.-F.1; Leung C.-H.1; Ma D.-L.1
2011-06-01
Source PublicationBiochimie
ISSN03009084 61831638
Volume93Issue:6Pages:1055-1064
AbstractG-quadruplexes are non-canonical DNA secondary structures putatively present in the promoter regions of oncogenes in the human genome. The targeting of promoter G-quadruplex structures to repress oncogene transcription represents a potential anticancer strategy. Here, we have used high-throughput virtual screening to identify FDA-approved drug methylene blue (MB) as a promising scaffold for binding the c-myc oncogene G-quadruplex DNA. Based on molecular docking analysis of MB to the c-myc G-quadruplex, we designed and screened 50 MB derivatives containing side chains that could interact with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring compounds were synthesized and the interactions with the c-myc G-quadruplex were investigated using the FID assay. The results showed that the methylene blue derivatives 6a-c were able to bind to the c-myc G-quadruplex with greater binding affinity compared to the known G-quadruplex binding ligand, crystal violet. The activity of the most potent compound identified from the FID assay, 6b, as an inhibitor for polymerase-drive DNA extension was examined using a PCR-stop assay and compared against that of the parent compound methylene blue. The results of the PCR-stop assay showed that the addition of the side chain improved the activity of the derivatives as an inhibitor compared to the parent compound. The MB derivative 6b was shown to be highly selective towards c-myc G-quadruplex over double-stranded DNA and other biologically relevant G-quadruplexes using UV-visible spectroscopy and mass spectrometry, respectively. The MB derivative 6b could induce or stabilize c-myc G-quadruplex formation in both cell-free and cellular biological models, and displayed higher cytoxicity against human hepatocarcinoma cells compared to the parent compound, MB. © 2011 Elsevier Masson SAS. All rights reserved.
Keywordc-myc G-quadruplex FDA-approved drug Methylene blue Repurposing Structure-based optimization
DOI10.1016/j.biochi.2011.02.013
URLView the original
Language英語
Fulltext Access
Citation statistics
Cited Times [WOS]:65   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Hong Kong Baptist University
2.City University of Hong Kong
Recommended Citation
GB/T 7714
Chan D.S.-H.,Yang H.,Kwan M.H.-T.,et al. Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer[J]. Biochimie,2011,93(6):1055-1064.
APA Chan D.S.-H..,Yang H..,Kwan M.H.-T..,Cheng Z..,Lee P..,...&Ma D.-L..(2011).Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer.Biochimie,93(6),1055-1064.
MLA Chan D.S.-H.,et al."Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer".Biochimie 93.6(2011):1055-1064.
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Chan D.S.-H.]'s Articles
[Yang H.]'s Articles
[Kwan M.H.-T.]'s Articles
Baidu academic
Similar articles in Baidu academic
[Chan D.S.-H.]'s Articles
[Yang H.]'s Articles
[Kwan M.H.-T.]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Chan D.S.-H.]'s Articles
[Yang H.]'s Articles
[Kwan M.H.-T.]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.