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Article: Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer

TitleStructure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer
Authors
Issue Date2011
PublisherElsevier France, Editions Scientifiques et Medicales. The Journal's web site is located at http://www.elsevier.com/locate/biochi
Citation
Biochimie, 2011, v. 93 n. 6, p. 1055-1064 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/168523
ISSN
2015 Impact Factor: 2.474
2015 SCImago Journal Rankings: 1.462
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorChan, DSHen_US
dc.contributor.authorYang, Hen_US
dc.contributor.authorKwan, MHTen_US
dc.contributor.authorCheng, Zen_US
dc.contributor.authorLee, Pen_US
dc.contributor.authorBai, LPen_US
dc.contributor.authorJiang, ZHen_US
dc.contributor.authorWong, CYen_US
dc.contributor.authorFong, WFen_US
dc.contributor.authorLeung, CHen_US
dc.contributor.authorMa, DLen_US
dc.date.accessioned2012-10-08T03:20:01Z-
dc.date.available2012-10-08T03:20:01Z-
dc.date.issued2011en_US
dc.identifier.citationBiochimie, 2011, v. 93 n. 6, p. 1055-1064en_US
dc.identifier.issn0300-9084en_US
dc.identifier.urihttp://hdl.handle.net/10722/168523-
dc.description.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.en_US
dc.languageengen_US
dc.publisherElsevier France, Editions Scientifiques et Medicales. The Journal's web site is located at http://www.elsevier.com/locate/biochien_US
dc.relation.ispartofBiochimieen_US
dc.subject.meshAntineoplastic Agents - Chemical Synthesis - Pharmacologyen_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshDrug Approvalen_US
dc.subject.meshG-Quadruplexes - Drug Effectsen_US
dc.subject.meshGene Expression Regulation - Drug Effectsen_US
dc.subject.meshGenes, Reporteren_US
dc.subject.meshGenes, Mycen_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHep G2 Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshLuciferases - Biosynthesis - Geneticsen_US
dc.subject.meshMethylene Blue - Analogs & Derivatives - Chemical Synthesis - Chemistry - Pharmacologyen_US
dc.subject.meshMolecular Dynamics Simulationen_US
dc.subject.meshPromoter Regions, Geneticen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleStructure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizeren_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.emailMa, DL:edmondma@hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.identifier.authorityMa, DL=rp00760en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.biochi.2011.02.013en_US
dc.identifier.pmid21377506-
dc.identifier.scopuseid_2-s2.0-79955065928en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955065928&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume93en_US
dc.identifier.issue6en_US
dc.identifier.spage1055en_US
dc.identifier.epage1064en_US
dc.identifier.isiWOS:000290974300010-
dc.publisher.placeFranceen_US
dc.identifier.scopusauthoridChan, DSH=35285471900en_US
dc.identifier.scopusauthoridYang, H=36653320200en_US
dc.identifier.scopusauthoridKwan, MHT=37039555100en_US
dc.identifier.scopusauthoridCheng, Z=37039284500en_US
dc.identifier.scopusauthoridLee, P=37100150400en_US
dc.identifier.scopusauthoridBai, LP=35995180600en_US
dc.identifier.scopusauthoridJiang, ZH=7404279415en_US
dc.identifier.scopusauthoridWong, CY=7404954160en_US
dc.identifier.scopusauthoridFong, WF=7102816013en_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridMa, DL=7402075538en_US
dc.identifier.citeulike8964366-

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