Stabilization of G-quadruplex DNA with platinum(II) Schiff base complexes: luminescent probe and down-regulation of c-myc oncogene expression.
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 muM) 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 lambda(max)=652 nm. Complex 3 also effectively down-regulated the expression of c-myc in human hepatocarcinoma cells.
Wu
Peng
P
Department of Chemistry and Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Ma
Dik-Lung
DL
Leung
Chung-Hang
CH
Yan
Siu-Cheong
SC
Zhu
Nianyong
N
Abagyan
R
R
Che
Chi-Ming
CM
D001483:Base Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D015536:Down-Regulation / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D049449:Luminescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012545:Schiff Bases / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
C546674:N,N'-bis(4-(1-(2-propylpiperidine)oxy)salicylidene)-4,5-methoxy-1,2-phenylenediamine Pt(II); D009944:Organoplatinum Compounds; D016271:Proto-Oncogene Proteins c-myc; D012545:Schiff Bases; D010984:Platinum