期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 118, 期 -, 页码 266-275出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.04.030
关键词
Anticancer therapeutics; G-quadruplex; Western blot; Telomerase activity; c-MyC
资金
- NSF [CHE 1518006]
- UMD Graduate Dean's Dissertation Fellowship
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1518006] Funding Source: National Science Foundation
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1264509] Funding Source: National Science Foundation
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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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