Rational Design of Substituted Diarylureas: a Scaffold for Binding to G-quadruplex Motifs

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2008 Dec 5

PMID 19053833

Citations 9

Authors

William C Drewe

Rupesh Nanjunda

Mekala Gunaratnam

Monica Beltran

Gary N Parkinson

Anthony P Reszka

W David Wilson

Stephen Neidle

Affiliations

Soon will be listed here.

Abstract

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.

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