Premium
Tetrasubstituted Phenanthrolines as Highly Potent, Water‐Soluble, and Selective G‐Quadruplex Ligands
Author(s) -
Larsen Anders Foller,
Nielsen Mads Corvinius,
Ulven Trond
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200081
Subject(s) - circular dichroism , chemistry , förster resonance energy transfer , combinatorial chemistry , electrospray ionization , hela , g quadruplex , phenanthroline , mass spectrometry , benzimidazole , intercalation (chemistry) , small molecule , molecule , selectivity , fluorescence , stereochemistry , dna , crystallography , organic chemistry , chromatography , in vitro , biochemistry , physics , quantum mechanics , catalysis
Small molecules capable of stabilizing the G‐quadruplex (G4) structure are of interest for the development of improved anticancer drugs. Novel 4,7‐diamino‐substituted 1,10‐phenanthroline‐2,9‐dicarboxamides that represent hybrid structures of known phenanthroline‐based ligands have been designed. An efficient synthetic route to the compounds has been developed and their interactions with various G4 sequences have been evaluated by Förster resonance energy transfer (FRET) melting assays, fluorescent intercalator displacement (FID), electrospray ionization mass spectrometry (ESI‐MS), and circular dichroism (CD) spectroscopy. The preferred compounds have high aqueous solubility and are strong and potent G4 binders with a high selectivity over duplex DNA; thus, they represent a significant improvement over the lead compounds. Two of the compounds are inhibitors of HeLa and HT1080 cell proliferation.