Stabilization of G-quadruplex DNA with platinum(II) Schiff base complexes: luminescent probe and down-regulation of c-myc oncogene expression

Chemistry. 2009 Dec 7;15(47):13008-21. doi: 10.1002/chem.200901943.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line
  • Crystallography, X-Ray
  • Down-Regulation / drug effects
  • G-Quadruplexes / drug effects*
  • Genes, myc
  • Humans
  • Luminescence
  • Models, Molecular
  • Molecular Sequence Data
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / metabolism
  • Organoplatinum Compounds / pharmacology
  • Platinum / chemistry*
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / chemistry*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Schiff Bases / chemistry*
  • Schiff Bases / metabolism
  • Schiff Bases / pharmacology

Substances

  • N,N'-bis(4-(1-(2-propylpiperidine)oxy)salicylidene)-4,5-methoxy-1,2-phenylenediamine Pt(II)
  • Organoplatinum Compounds
  • Proto-Oncogene Proteins c-myc
  • Schiff Bases
  • Platinum