UM
Structure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA
Wang P.1; Leung C.-H.1; Ma D.-L.1; Yan S.-C.1; Che C.-M.1
2010-06-18
Source PublicationChemistry - A European Journal
ISSN09476539 15213765
Volume16Issue:23Pages:6900-6911
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 Pt-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 ([PtL2R]; L2 = 2,6bis[1-(3-piperidinepropyl)-1H-enzo[d]imidazol-2-yl]pyridine, R = Cl) displayed the strongest inhibition in a cell-free system (IC = 2.2 μM) and was 3.3-fold more potent than that of 1. Complexes 3a and 4a ([PtL3R]; 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 IC 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 10-10dm mol, 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.
KeywordDNA structures Gquadruplexes Ligand effects Oncogenes Platinum
DOI10.1002/chem.201000167
URLView the original
Language英語
Fulltext Access
Citation statistics
Cited Times [WOS]:107   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Institute of Molecular Technology for Drug Discovery and Synthesis, Hong Kong
2.Hong Kong Baptist University
Recommended Citation
GB/T 7714
Wang P.,Leung C.-H.,Ma D.-L.,et al. Structure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA[J]. Chemistry - A European Journal,2010,16(23):6900-6911.
APA Wang P.,Leung C.-H.,Ma D.-L.,Yan S.-C.,&Che C.-M..(2010).Structure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA.Chemistry - A European Journal,16(23),6900-6911.
MLA Wang P.,et al."Structure-based design of platinum(II) Complexes as c-myc oncogene Down-regulators and luminescent probes for G-quadruplex DNA".Chemistry - A European Journal 16.23(2010):6900-6911.
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
[Wang P.]'s Articles
[Leung C.-H.]'s Articles
[Ma D.-L.]'s Articles
Baidu academic
Similar articles in Baidu academic
[Wang P.]'s Articles
[Leung C.-H.]'s Articles
[Ma D.-L.]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Wang P.]'s Articles
[Leung C.-H.]'s Articles
[Ma D.-L.]'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.