Photoactivatable platinum(II) terpyridine derivatives for G-quadruplex DNA double anchoring

Abstract

Platinum(II) tolylterpyridine (ttpy) complexes, have been shown to generate monofunctional adducts with various G-quadruplex DNA forming sequences resulting from an efficient π-stacking mode on the top of the quadruplex structure. To further explore the potential of this series with regard to quadruplex recognition, classical photocrosslinking groups (benzophenone, tetraphenylazide) have been grafted on the tolylterpyridine ligand moiety, thereby generating two new derivatives Pt-ttpy-Bn and Pt-ttpy-N3. Evaluation of their non-covalent binding for G-quadruplex DNA has been performed by FRET-melting and FID assays using two G-quadruplex matrices i.e. the telomeric sequence 22AG and the oncogene promotor sequence c-myc, which revealed high affinity and improved selectivity as compared to the parent compound. Subsequently the capacity of the compounds to establish one or two anchorage points (one by platination, one by photoinduced crosslinking) with the quadruplexes has been studied by gel electrophoresis with and without photoactivation. Interestingly both compounds do platinate the quadruplexes studied with high selectivity as the platination yield is poorly affected by the presence of duplex competitor. By contrast, only the azido derivative Pt-ttpy-N3 was found to form a second covalent bond within the G-quadruplexes upon photoactivation indicating a higher confinement of the crosslinking moiety in this case. Finally the two compounds exhibit poor cytotoxicity in the dark on two cancer cell lines (A2780 and HT29), whereas that of the benzophenone derivative is significantly enhanced upon irradiation. Altogether the two new compounds represent novel prototypes usable for trapping G4 DNA alone or eventually G4-DNA protein interactions in complex in vitro systems or in cells.