Tetrasubstituted phenanthrolines as highly potent, water-soluble, and selective g-quadruplex ligands

TY - JOUR

T1 - Tetrasubstituted phenanthrolines as highly potent, water-soluble, and selective g-quadruplex ligands

AU - Larsen, Anders Foller

AU - Nielsen, Mads Corvinius

AU - Ulven, Trond

N1 - Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2012/8/27

Y1 - 2012/8/27

N2 - 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. Combine and conquer: The synthesis of a series of tetrasubstituted phenanthrolines, representing hybrids of two classes of quadruplex binders, is described. Screening on structurally diverse G-quadruplexes resulted in the identification of ligands possessing the best properties from both lead compounds: good aqueous solubility, a strong and potent G-quadruplex binding with selectivity over duplex DNA, and cytotoxic activity on two cancer cell lines (see scheme).

AB - 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. Combine and conquer: The synthesis of a series of tetrasubstituted phenanthrolines, representing hybrids of two classes of quadruplex binders, is described. Screening on structurally diverse G-quadruplexes resulted in the identification of ligands possessing the best properties from both lead compounds: good aqueous solubility, a strong and potent G-quadruplex binding with selectivity over duplex DNA, and cytotoxic activity on two cancer cell lines (see scheme).

U2 - 10.1002/chem.201200081

DO - 10.1002/chem.201200081

M3 - Journal article

SN - 0947-6539

VL - 18

SP - 10892

EP - 10902

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 35

ER -