Stabilization of G‐Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down‐Regulation of c‐ myc Oncogene Expression
Author(s) -
Wu Peng,
Ma DikLung,
Leung ChungHang,
Yan SiuCheong,
Zhu Nianyong,
Abagyan R.,
Che ChiMing
Publication year - 2009
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.200901943
Subject(s) - g quadruplex , chemistry , dna , schiff base , titration , stacking , stereochemistry , docking (animal) , biochemistry , inorganic chemistry , organic chemistry , medicine , nursing
Abstract The interactions of a series of platinum(II) Schiff base complexes with c‐ myc G‐quadruplex DNA were studied. Complex [PtL 1a ] ( 1 a ; H 2 L 1a = N , N ′‐bis(salicylidene)‐4,5‐methoxy‐1,2‐phenylenediamine) can moderately inhibit c‐ myc gene promoter activity in a cell‐free system through stabilizing the G‐quadruplex structure and can inhibit c‐ myc oncogene expression in cultured cells. The interaction between 1 a and G‐quadruplex DNA has been examined by 1 H NMR spectroscopy. By using computer‐aided structure‐based drug design for hit‐to‐lead optimization, an in silico G‐quadruplex DNA model has been constructed for docking‐based virtual screening to develop new platinum(II) Schiff base complexes with improved inhibitory activities. Complex [PtL 3 ] ( 3 ; H 2 L 3 = N , N ′‐bis{4‐[1‐(2‐propylpiperidine)oxy]salicylidene}‐4,5‐methoxy‐1,2‐phenylenediamine) has been identified with a top score in the virtual screening. This complex was subsequently prepared and experimentally tested in vitro for its ability to stabilize or induce the formation of the c ‐myc G‐quadruplex. The inhibitory activity of 3 (IC 50 =4.4 μ M ) is tenfold more than that of 1 a . The interaction between 1 a or 3 with c‐ myc G‐quadruplex DNA has been examined by absorption titration, emission titration, molecular modeling, and NMR titration experiments, thus revealing that both 1 a and 3 bind c‐ myc G‐quadruplex DNA through an external end‐stacking mode at the 3’ terminal face of the G‐quadruplex. Such binding of G‐quadruplex DNA with 3 is accompanied by up to an eightfold increase in the intensity of photoluminescence at λ max =652 nm. Complex 3 also effectively down‐regulated the expression of c‐ myc in human hepatocarcinoma cells.