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

• DOI: 10.1016/j.ejmech.2016.04.030
• Publication Date: 2016-04-29T19:08:52Z
• Authors: Changhao Wang; Brandon Carter-Co...; Yixuan Du; Jie Zhou; Musabbir A. Saeed; Jinbing Liu; Min Guo; Benjamin Roembke; Clinton Mikek; Edwin A. Lewis; Rena G. Lapidus; Herman O. Sintim
• Keywords: Pharmacology; 0301 basic medicine; 0303 health sciences; Base Sequence; Cell Survival; Organic Chemistry; Antineoplastic Agents; 3. Good health; G-Quadruplexes; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; Alkynes; Cell Line, Tumor; Drug Discovery; Humans; Diminazene; Telomerase

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.