Rational design of substituted diarylureas: a scaffold for binding to G-quadruplex motifs.
The design and synthesis of a series of urea-based nonpolycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents are described. Their interactions with quadruplexes have been examined by means of fluorescent resonance energy transfer melting, circular dichroism, and surface plasmon resonance-based assays. These validate the design concept for such urea-based ligands and also show that they have significant selectivity over duplex DNA, as well as for particular G-quadruplexes. The ligand-quadruplex complexes were investigated by computational molecular modeling, providing further information on structure-activity relationships. Preliminary biological studies using short-term cell growth inhibition assays show that some of the ligands have cancer cell selectivity, although they appear to have low potency for intracellular telomeric G-quadruplex structures, suggesting that their cellular targets may be other, possibly oncogene-related quadruplexes.
Drewe
William C
WC
The Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Nanjunda
Rupesh
R
Gunaratnam
Mekala
M
Beltran
Monica
M
Parkinson
Gary N
GN
Reszka
Anthony P
AP
Wilson
W David
WD
Neidle
Stephen
S
D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D013816:Thermodynamics; D014508:Urea / Q000737:chemistry*
D007364:Intercalating Agents; D008024:Ligands; D014508:Urea; D004247:DNA