2. Academic Validation
  3. Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities

Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities

  • Eur J Med Chem. 2016 Aug 8:118:266-75. doi: 10.1016/j.ejmech.2016.04.030.
Changhao Wang 1,  Brandon Carter-Cooper 2,  Yixuan Du 1,  Jie Zhou 3,  Musabbir A Saeed 1,  Jinbing Liu 1,  Min Guo 1,  Benjamin Roembke 1,  Clinton Mikek 4,  Edwin A Lewis 4,  Rena G Lapidus 2,  Herman O Sintim 5
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
  • 2 Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
  • 3 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA; Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA; Center for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA.
  • 4 Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA.
  • 5 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA; Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA; Center for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA. Electronic address: hsintim@purdue.edu.
PMID: 27132164 DOI: 10.1016/j.ejmech.2016.04.030
Abstract

G-quadruplex ligands have been touted as potential Anticancer agents, however, none of the reported G-quadruplex-interactive small molecules have gone past phase II clinical trials. Recently it was revealed that diminazene (berenil, DMZ) actually binds to G-quadruplexes 1000 times better than DNA duplexes, with dissociation constants approaching 1 nM. DMZ however does not have strong Anticancer activities. In this paper, using a panel of biophysical tools, including NMR, FRET melting assay and FRET competition assay, we discovered that monoamidine analogues of DMZ bearing alkyne substitutes selectively bind to G-quadruplexes. The lead DMZ analogues were shown to be able to target c-MYC G-quadruplex both in vitro and in vivo. Alkyne DMZ analogues display respectable Anticancer activities (single digit micromolar GI50) against ovarian (OVCAR-3), prostate (PC-3) and triple negative breast (MDA-MB-231) Cancer cell lines and represent interesting new leads to develop Anticancer agents.

Keywords

Anticancer therapeutics; G-quadruplex; Telomerase activity; Western blot; c-MyC.

Figures