Rational Design of Substituted Diarylureas: A Scaffold for Binding to G-Quadruplex Motifs

Abstract

The design and synthesis of a series of urea-based non-polycyclic aromatic ligands with alkylaminoanilino side chains as telomeric and genomic G-quadruplex DNA interacting agents is 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 for compared to 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.

Design of Modular G‐quadruplex Ligands

“…A series of diarylurea derivatives lacking the 1,2,3‐triazole moiety (i.e., 5 – 7 ) have also been synthesized . Molecular modeling studies predict that the urea oxygen atom is located over the ion channel of the G‐quadruplex, as in the previous series, resulting in optimal positioning of the diphenylurea moiety for π stacking on the G‐quartet and allowing the side chains to penetrate the G4 grooves.…”

Crystallographic investigation into the self-assembly, guest binding, and flexibility of urea functionalised metal-organic frameworks

“…The urea-dicarboxylate ligand, LH 2 , was prepared on the gram scale according to a modification of a literature procedure in two steps from t-butyl 4-aminobenzoate and carbonyldiimidazole (49) 3 ] n . The material consists of chains of L 2-molecules connected by seven-coordinate Cd 2+ cations with distorted pentagonal bipyramidal geometry (Figure 2(a)).…”

Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

“…Further biophysical experiments revealed that the electrostatic surface of M2 was similar to 307A and 12459 and plays an important role in end-stacking binding to the G-quadruplex [65]. The great bioactivity of these compounds has promoted the development of various types of similar compounds, such as pyrimidine linked bisaryl compounds [66], urea linked bis-phenyl compounds [67], bisphenanthrolines [68] and bis-benzimidazoles [69]. …”