8 Extensive polymorphism is observed among G-quadruplexes, depending on the environmental conditions, and associated with different orientations of the four contributing strands, as well as the type, length and sequence of their interconnecting loops. G-quartet π-π stacking-type accumulation is responsible for the G-quadruplex core assembly.

G-quartets are further reinforced by guanine carbonyl coordination to (monovalent) cations. G-quadruplexes are tetraplex helices, assembled from guanine (G)-rich DNA or RNA sequences, in which the presence of repetitive guanine tracts enables formation of square planar G-quartets via Hoogsteen-face hydrogen bonding. Over the last decade, the family of non-canonical nucleic acid topologies known as G-quadruplexes have become the object of a vast number of studies, owing to their emerging biological roles, including telomerase inhibition, 1 involvement in chromatin remodelling, 2 epigenetic alteration 3 and genome instability, 4 as well as regulation of replication, 5 transcription 6 and translation. ‘closed’), as well as the relative contributions to affinity from end-stacking and H-bonding, are highly dependent on the nature of the interacting Pt-complex side-chain. Docking simulations were conducted to provide insights into the binding modes for the same four Pt-compounds, suggesting that the binding preference for two alternative orientations of the c-myc G-quadruplex thymine ‘cap’ (‘open’ vs. To gain direct evidence of the nature of the interactions, mixtures of c-myc with the four most promising compounds were studied via UV Resonance Raman (UVRR) spectroscopy, which revealed end-stacking binding mode, combined with interactions of side-chains with loop nucleobase residues. The same study implied contributions of the diverse side-chains to helix stabilization. A c-myc DNA-melting experiment showed significant stabilizing abilities for all compounds, with the most potent binder, the morpholine-Pt-complex, exhibiting a ΔT m>30 ☌, at 1 : 5 DNA-to-ligand molar ratio. Remarkable emission enhancements (up to 200-fold) upon addition of excess DNA were demonstrated by a subset of the compounds with c-myc, providing a basis for optical selectivity, since optical response to all other tested DNAs was low. All compounds exhibited binding selectivity in favour of c-myc, with association constants (K a) in the range of 2–5×10 5 M −1, lower affinity for both folds of 22AG and for ds26 and negligible affinity for polyT. The binding affinities of the Pt-complexes were evaluated via UV-vis and fluorescence titrations, against 5 topologically-distinct DNA structures, including c-myc G-quadruplex, two telomeric (22AG) G-quadruplexes, a duplex (ds26) and a single-stranded (polyT) DNA. These include a di-isopropyl carbamoyl amide, a morpholine ethylenamide, two enantiomeric proline imides and an oxazole. We report the efficient synthesis of a family of organoplatinum(II) complexes, featuring a 2-(-6-yl)phenyl tridentate (N ∧N ∧C) ligand, that incorporates peripheral side-chains aiming at enhancing and diversifying its interaction capabilities. Organometallic molecules offer some of the most promising scaffolds for interaction with G-quadruplex nucleic acids.

Gaining insights