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

Changhao Wang; Brandon Carter-Cooper; Yixuan Du; Jie Zhou; Musabbir A Saeed; Jinbing Liu; Min Guo; Benjamin Roembke; Clinton Mikek; Edwin A Lewis; Rena G Lapidus; Herman O Sintim

doi:10.1016/j.ejmech.2016.04.030

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. Epub 2016 Apr 20.

Authors

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.

MeSH terms

Alkynes / chemistry*
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism*
Antineoplastic Agents / pharmacology*
Base Sequence
Cell Line, Tumor
Cell Survival / drug effects
Diminazene / chemistry
Diminazene / metabolism*
Diminazene / pharmacology*
G-Quadruplexes*
Humans
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Telomerase / antagonists & inhibitors

Substances

Alkynes
Antineoplastic Agents
Proto-Oncogene Proteins c-myc
Telomerase
Diminazene