Exploring the Differential Recognition of DNA G-Quadruplex Targets by Small Molecules Using Dynamic Combinatorial Chemistry (original) (raw)
2008, Angewandte Chemie International Edition
The search for small-molecule ligands of biological targets remains a challenge with major implications for both fundamental studies and drug discovery.[1] We are interested in the discovery of small molecules that specifically interact with regulatory nucleic acid elements. Such molecules have the potential to alter the expression of particular genes and thus influence cellular functions. Certain guanine-rich (G-rich) regions in genomic DNA can form four-stranded structures, called G quadruplexes, which have emerged as biologically important elements.[2] Gquadruplex formation has been linked to cancer-related biology, most notably by remodeling of the telomere structure or by the regulation of oncogenic expression.[3] The two key challenges in the design of small-molecule[4] ligands for quadruplex DNA are: 1) to attain specificity for G-quadruplex-forming sequences over duplex DNA and 2) to achieve specificity for a given G-quadruplex structure and/or G-quadruplex-forming sequence. The latter criterion has become more important in the light of the recently revealed prevalence of G-quadruplex-forming sequences in the human genome,[5a,b] and particularly in promoter regions.[5c] Although G quadruplexes all contain G quartets, there is considerable scope for structural variations within the loop and groove regions,[6] suggesting that specificity in the molecular recognition of a quadruplex is attainable. However, the rational design of quadruplexbinding molecules requires a good understanding of the interactions between the ligand and its host. Owing to the paucity of structural data and the dynamic nature of G quadruplexes, combinatorial searches are appealing. Herein, we report on a study that employs a dynamic combinatorial approach to explore the differential recognition of G-quadruplex targets by closely related small molecules. Dynamic combinatorial chemistry (DCC) is a powerful approach for the rapid identification of binders for small molecules and biological targets.[7] Owing to its adaptive nature, small changes in the composition of a dynamic combinatorial library (DCL) upon introduction of a ** This study was supported by the Cancer Research UK, the EU, and EPSRC. We thank the EPSRC Mass Spectrometry Service for mass analysis.
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