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

Abstract

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. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.