TY - JOUR
T1 - Stabilization of G-quadruplex DNA with platinum(II) Schiff base complexes
T2 - Luminescent probe and down-regulation of c-myc oncogene expression
AU - Wu, Peng
AU - Ma, Dik-Lung
AU - Leung, Chung-Hang
AU - Yan, Siu-Cheong
AU - Zhu, Nianyong
AU - Abagyan, R.
AU - Che, Chi-Ming
N1 - Funding Information:
This work was supported by the Area of Excellence Scheme established under the University Grants Committee (HKSAR, China (AoE/P-10/01), the University of Hong Kong (University Development Fund), and The Chinese Academy of Sciences-Croucher Foundation Funding Scheme For Joint Laboratories.
Publisher copyright:
© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2009/12/7
Y1 - 2009/12/7
N2 - The interactions of a series of platinum(II) Schiff base complexes with c-myc G-quadruplex DNA were studied. Complex [PtL1a] (1a; H 2L1a= 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 1a and G-quadruplex DNA has been examined by 1H 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 [PtL3] (3; H2L 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 (IC50 = 4.4 μm) is tenfold more than that of 1a. The interaction between 1a 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 1a 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 λmax = 652 nm. Complex 3 also effectively down-regulated the expression of c-myc in human hepatocarcinoma cells.
AB - The interactions of a series of platinum(II) Schiff base complexes with c-myc G-quadruplex DNA were studied. Complex [PtL1a] (1a; H 2L1a= 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 1a and G-quadruplex DNA has been examined by 1H 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 [PtL3] (3; H2L 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 (IC50 = 4.4 μm) is tenfold more than that of 1a. The interaction between 1a 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 1a 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 λmax = 652 nm. Complex 3 also effectively down-regulated the expression of c-myc in human hepatocarcinoma cells.
KW - G-quadruplex DNA
KW - Luminescent probes
KW - Onogenes
KW - Platinum
KW - Schiff bases
UR - http://www.scopus.com/inward/record.url?scp=73349096880&partnerID=8YFLogxK
U2 - 10.1002/chem.200901943
DO - 10.1002/chem.200901943
M3 - Journal article
AN - SCOPUS:73349096880
SN - 0947-6539
VL - 15
SP - 13008
EP - 13021
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 47
ER -