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

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

来源：European Journal of Medicinal Chemistry, 2016, 118: 266-275.

DOI：10.1016/j.ejmech.2016.04.030

• Anticancer therapeutics
• G-quadruplex
• Western blot
• Telomerase activity
• c-MyC

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 GI(50)) 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.

• 出版日期2016-8-8