An Octahedral Cobalt(III) Complex with Axial NH₃ Ligands that Templates and Selectively Stabilises G‐quadruplex DNA

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.

On the G‐Quadruplex Binding of a New Class of Nickel(II), Copper(II), and Zinc(II) Salphen‐Like Complexes

“…Upon addition of increasing amounts of our compounds, we found that, while 3 interacts with the CT‐DNA inducing no conformational changes (Figure S7c), both 1 and 2 slightly modify the secondary structure of the oligonucleotide, as assessed by the marginal variations of its diagnostic CD bands (Figure S7a,b). Furthermore, an increase of the positive band and a decrease of the negative CD signal in hTelo solution was recorded in the presence of 1–3 (Figure S7d–e), suggesting a minor conformational change of its secondary structure, as already reported for other metal complexes [9,12b,20] No significant changes were detected in c‐myc solutions (Figure S7g–i).…”

Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound

“…Nickel(II) salphen 1 and cobalt(III) salphens 3a and 3d were synthesised following a previously reported procedure. 48,49 The new platinum(II) and cobalt(III) salphens 2, 3b, 3c and 3e, and cobalt(III) salnaphs 4a-4e were synthesised by first reacting 4-(4-formyl-3-hydroxyphenoxy)-N,N,N-trimethylethan-1-ammonium bromide with 1,2-phenylendiamine and 2,3-diaminonaphthalene respectively (Scheme 1). Platinum(II) complex 2 was obtained by reacting the salphen ligand with K 2 PtCl 4 .…”

Interaction of Metal Complexes with G‐Quadruplexes

“…84 Moreover, in order to avoid the platination of adenine bases located in the loops, the extension of the aromaticity of the ligands has been developed (dibenzoterpy, bis(benzimidazole)pyridine) and these modified terpyridine complexes show increased affinities towards G4. 83 For example, a series of platinum(II) complexes containing 2,6-bis(benzimidazol-2yl)pyridine (bzimpy) (60-63) and 2,6-bis(pyrazol-3-yl)pyridine scaffolds with amine side chains (64)(65) were found to display high selectivity towards c-myc G4 DNA and not duplex DNA. They also showed significant inhibition of c-myc gene transcription in cultured cells, presumably through the stabilization of the G4 structure.…”