Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands

Bioorg Med Chem. 2012 May 1;20(9):2829-36. doi: 10.1016/j.bmc.2012.03.031. Epub 2012 Mar 21.

Abstract

A series of 1,8-dipyrazolcarbazole (DPC) derivatives (6a-6d, 7a-7d) designed as G-quadruplex ligands have been synthesized and characterized. The FRET-melting and SPR results showed that the DPC derivatives could well recognize G-quadruplex with strong discrimination against the duplex DNA. In addition, the DPC derivatives showed much stronger stabilization activities and binding affinities for c-myc G-quadruplex rather than telomeric G-quadruplex. Therefore, their interactions with c-myc G-quadruplex were further explored by means of CD spectroscopy, PCR-stop assay, and molecular modeling. In cellular studies, all compounds showed strong cytotoxicity against cancer cells, while weak cytotoxicity towards normal cells. RT-PCR assay showed that compound 7b could down-regulate c-myc gene expression in Ramos cell line, while had no effect on c-myc expression in CA46 cell line with NHE III(1) element removed, indicating its effective binding with G-quadruplex on c-myc oncogene in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / chemical synthesis
  • Carbazoles / chemistry*
  • Carbazoles / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Circular Dichroism
  • Down-Regulation
  • Fluorescence Resonance Energy Transfer
  • G-Quadruplexes*
  • HL-60 Cells
  • Hep G2 Cells
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Surface Plasmon Resonance

Substances

  • Carbazoles
  • Ligands
  • Proto-Oncogene Proteins c-myc
  • carbazole