Premium
Structure‐Based Design of Platinum(II) Complexes as c‐ myc Oncogene Down‐Regulators and Luminescent Probes for G‐Quadruplex DNA
Author(s) -
Wang Ping,
Leung ChungHang,
Ma DikLung,
Yan SiuCheong,
Che ChiMing
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201000167
Subject(s) - pyridine , chemistry , g quadruplex , dna , stereochemistry , in silico , cancer cell , gene , cancer , biochemistry , medicinal chemistry , biology , genetics
A series of platinum(II) complexes with tridentate ligands was synthesized and their interactions with G‐quadruplex 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 cell‐free system. An in silico G‐quadruplex DNA model has been constructed for structure‐based virtual screening to develop new Pt II ‐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 3 a ([Pt II L2R ] + ; L2 =2,6‐bis[1‐(3‐piperidinepropyl)‐1 H ‐enzo[ d ]imidazol‐2‐yl]pyridine, R =Cl) displayed the strongest inhibition in a cell‐free system (IC 50 =2.2 μ M ) and was 3.3‐fold more potent than that of 1 . Complexes 3 a and 4 a ([Pt II L3R ] + ; L3 =2,6‐bis[1‐(3‐morpholinopropyl)‐1 H ‐pyrazol‐3‐yl]pyridine, R =Cl) were found to effectively inhibit c‐ myc gene expression in human hepatocarcinoma cells with IC 50 values of ≈17 μ M , whereas initial hit 1 displayed no significant effect on gene expression at concentrations up to 50 μ M . Complexes 3 a and 4 a have a strong preference for G‐quadruplex DNA over duplex DNA, as revealed by competition dialysis experiments and absorption titration; 3 a and 4 a bind G‐quadruplex DNA with binding constants ( K ) of approximately 10 6 –10 7 dm 3 mol −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 3 b is accompanied by an increase of up to 38‐fold in photoluminescence intensity at λ max =622 nm.