Tetrasubstituted phenanthrolines as highly potent, water-soluble, and selective G-quadruplex ligands.
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.
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
Anders Foller
AF
Larsen
Mads Corvinius
MC
Nielsen
Trond
T
Ulven
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000737:chemistry*; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013816:Thermodynamics; D014867:Water
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D008024:Ligands; D010618:Phenanthrolines; D014867:Water