Structure‐Based Design of Platinum(II) Complexes as c‐<i>myc</i> Oncogene Down‐Regulators and Luminescent Probes for G‐Quadruplex DNA

Chemistry - A European Journal - Tập 16 Số 23 - Trang 6900-6911 - 2010
Ping Wang1, Chung‐Hang Leung1, Dik‐Lung Ma2,1, Siu‐Cheong Yan1, Chi‐Ming Che1
1Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong (P.R. China),
2Current address: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong (P.R. China)

Tóm tắt

AbstractA 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 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 3 a ([PtIIL2R]+; L2=2,6‐bis[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 3 a and 4 a ([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 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 106–107 dm3 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 λmax=622 nm.

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Chemistry - A European Journal

Tập 16 Số 23

6900-6911

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