title: Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Changhao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Carter-Cooper
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Musabbir A
authors.initials: MA
authors.lastname: Saeed
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Jinbing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roembke
authors.affiliation: Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA.
authors.forename: Clinton
authors.initials: C
authors.lastname: Mikek
authors.affiliation: Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Lewis
authors.affiliation: Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.affiliation: 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.
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004133:Diminazene / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D054856:G-Quadruplexes; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase; D004133:Diminazene
keywords: Anticancer therapeutics; G-quadruplex; Telomerase activity; Western blot; c-MyC