| Institution: | 1. Department of Chemistry, Imperial College London, White City, London, W12 0BZ UK;2. Department of Chemistry, Imperial College London, White City, London, W12 0BZ UK
Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ UK;3. Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ UK |
| Abstract: | Guanine-rich sequences of DNA are known to readily fold into tetra-stranded helical structures known as G-quadruplexes (G4). Due to their biological relevance, G4s are potential anticancer drug targets and therefore there is significant interest in molecules with high affinity for these structures. Most G4 binders are polyaromatic planar compounds which π–π stack on the G4′s guanine tetrad. However, many of these compounds are not very selective since they can also intercalate into duplex DNA. Herein we report a new class of binder based on an octahedral cobalt(III) complex that binds to G4 via a different mode involving hydrogen bonding, electrostatic interactions and π–π stacking. We show that this new compound binds selectivity to G4 over duplex DNA (particularly to the G-rich sequence of the c-myc promoter). This new octahedral complex also has the ability to template the formation of G4 DNA from the unfolded sequence. Finally, we show that upon binding to G4, the complex prevents helicase Pif1-p from unfolding the c-myc G4 structure. |
