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Article: Structure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA

TitleStructure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA
Authors
KeywordsDNA structures
Gquadruplexes
Ligand effects
Oncogenes
Platinum
Issue Date2010
PublisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www.wiley-vch.de/home/chemistry
Citation
Chemistry - A European Journal, 2010, v. 16 n. 23, p. 6900-6911 How to Cite?
AbstractA series of platinum(II) complexes with tridentate ligands was synthesized and their interactions with Gquadruplex DNA within the c-myc gene promoter were evaluated. Complex 1, which has a flat planar 2,6-bis(benzimidazol-2-yl)pyridine (bzimpy) scaffold, was found to stabilize the c-myc G-quadruplex structure in a cellfree system. An in silico G-quadruplex DNA model has been constructed for structure-based virtual screening to develop new PtII-based complexes with superior inhibitory activities. By using complex 1 as the initial structure for hit-to-lead optimization, bzimpy and related 2,6-bis(pyrazol-3-yl) pyridine (dPzPy) scaffolds containing amine side-chains emerge as the top candidates. Six of the top-scoring complexes were synthesized and their interactions with c-myc G-quadruplex DNA have been investigated. The results revealed that all of the complexes have the ability to stabilize the c-myc G-quadruplex. Complex 3a ([PtIIL2R]+; L2 = 2,6bis[1-(3-piperidinepropyl)-1H-enzo[d]imidazol-2-yl]pyridine, R = Cl) displayed the strongest inhibition in a cell-free system (IC50 = 2.2 μM) and was 3.3-fold more potent than that of 1. Complexes 3a and 4a ([PtIIL3R]+; L3 = 2,6-bis[1-(3-morpholinopropyl)1H- pyrazol-3-yl]pyridine, R = Cl) were found to effectively inhibit c-myc gene expression in human hepatocarcinoma cells with IC50 values of 17 μM, whereas initial hit 1 displayed no significant effect on gene expression at concentrations up to 50 μM. Complexes 3a and 4a have a strong preference for Gquadruplex DNA over duplex DNA, as revealed by competition dialysis experiments and absorption titration; 3a and 4 a bind G-quadruplex DNA with binding constants (K) of approximately 106-107dm 3mol-1, which are at least an order of magnitude higher than the K values for duplex DNA. NMR spectroscopic titration experiments and molecular modeling showed that 4 a binds c-myc G-quadruplex DNA through an external end-stacking mode at the 3'terminal face of the G-quadruplex. Intriguingly, binding of c-myc G-quadruplex DNA by 3b is accompanied by an increase of up to 38-fold in photoluminescence intensity at λmax = 622 nm. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Persistent Identifierhttp://hdl.handle.net/10722/142059
ISSN
2015 Impact Factor: 5.771
2015 SCImago Journal Rankings: 2.323
ISI Accession Number ID
Funding AgencyGrant Number
The University of Hong Kong (University Development Fund)
Hong Kong Research Grant CouncilHKU 7052/07P
Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, ChinaAoE/P-10/01
Funding Information:

We are grateful for financial support from The University of Hong Kong (University Development Fund), the Hong Kong Research Grant Council (HKU 7052/07P), and the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (AoE/P-10/01).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWang, Pen_HK
dc.contributor.authorLeung, CHen_HK
dc.contributor.authorMa, DLen_HK
dc.contributor.authorYan, SCen_HK
dc.contributor.authorChe, CMen_HK
dc.date.accessioned2011-10-17T08:10:32Z-
dc.date.available2011-10-17T08:10:32Z-
dc.date.issued2010en_HK
dc.identifier.citationChemistry - A European Journal, 2010, v. 16 n. 23, p. 6900-6911en_HK
dc.identifier.issn0947-6539en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142059-
dc.description.abstractA series of platinum(II) complexes with tridentate ligands was synthesized and their interactions with Gquadruplex DNA within the c-myc gene promoter were evaluated. Complex 1, which has a flat planar 2,6-bis(benzimidazol-2-yl)pyridine (bzimpy) scaffold, was found to stabilize the c-myc G-quadruplex structure in a cellfree system. An in silico G-quadruplex DNA model has been constructed for structure-based virtual screening to develop new PtII-based complexes with superior inhibitory activities. By using complex 1 as the initial structure for hit-to-lead optimization, bzimpy and related 2,6-bis(pyrazol-3-yl) pyridine (dPzPy) scaffolds containing amine side-chains emerge as the top candidates. Six of the top-scoring complexes were synthesized and their interactions with c-myc G-quadruplex DNA have been investigated. The results revealed that all of the complexes have the ability to stabilize the c-myc G-quadruplex. Complex 3a ([PtIIL2R]+; L2 = 2,6bis[1-(3-piperidinepropyl)-1H-enzo[d]imidazol-2-yl]pyridine, R = Cl) displayed the strongest inhibition in a cell-free system (IC50 = 2.2 μM) and was 3.3-fold more potent than that of 1. Complexes 3a and 4a ([PtIIL3R]+; L3 = 2,6-bis[1-(3-morpholinopropyl)1H- pyrazol-3-yl]pyridine, R = Cl) were found to effectively inhibit c-myc gene expression in human hepatocarcinoma cells with IC50 values of 17 μM, whereas initial hit 1 displayed no significant effect on gene expression at concentrations up to 50 μM. Complexes 3a and 4a have a strong preference for Gquadruplex DNA over duplex DNA, as revealed by competition dialysis experiments and absorption titration; 3a and 4 a bind G-quadruplex DNA with binding constants (K) of approximately 106-107dm 3mol-1, which are at least an order of magnitude higher than the K values for duplex DNA. NMR spectroscopic titration experiments and molecular modeling showed that 4 a binds c-myc G-quadruplex DNA through an external end-stacking mode at the 3'terminal face of the G-quadruplex. Intriguingly, binding of c-myc G-quadruplex DNA by 3b is accompanied by an increase of up to 38-fold in photoluminescence intensity at λmax = 622 nm. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.en_HK
dc.languageeng-
dc.publisherWiley - V C H Verlag GmbH & Co KGaA. The Journal's web site is located at http://www.wiley-vch.de/home/chemistryen_HK
dc.relation.ispartofChemistry - A European Journalen_HK
dc.subjectDNA structuresen_HK
dc.subjectGquadruplexesen_HK
dc.subjectLigand effectsen_HK
dc.subjectOncogenesen_HK
dc.subjectPlatinumen_HK
dc.subject.meshDNA - chemistry-
dc.subject.meshDown-Regulation - drug effects-
dc.subject.meshG-Quadruplexes - drug effects-
dc.subject.meshOrganoplatinum Compounds - chemical synthesis - chemistry - pharmacology-
dc.subject.meshProto-Oncogene Proteins c-myc - chemistry - drug effects-
dc.titleStructure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNAen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0947-6539&volume=16&issue=23&spage=6900&epage=6911&date=2010&atitle=Structure-based+design+of+platinum(II)+complexes+as+c-myc+oncogene+down-regulators+and+luminescent+probes+for+G-quadruplex+DNA-
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_HK
dc.identifier.emailMa, DL:edmondma@hku.hken_HK
dc.identifier.emailChe, CM:cmche@hku.hken_HK
dc.identifier.authorityLeung, CH=rp00730en_HK
dc.identifier.authorityMa, DL=rp00760en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/chem.201000167en_HK
dc.identifier.pmid20437426-
dc.identifier.scopuseid_2-s2.0-77953563443en_HK
dc.identifier.hkuros181303-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77953563443&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue23en_HK
dc.identifier.spage6900en_HK
dc.identifier.epage6911en_HK
dc.identifier.isiWOS:000279856100023-
dc.publisher.placeGermanyen_HK
dc.relation.projectInstitute of molecular technology for drug discovery and synthesis-
dc.identifier.scopusauthoridWang, P=7405460611en_HK
dc.identifier.scopusauthoridLeung, CH=7402612570en_HK
dc.identifier.scopusauthoridMa, DL=7402075538en_HK
dc.identifier.scopusauthoridYan, SC=7401744858en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK
dc.identifier.citeulike7123850-

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