Targeting Guanine Quadruplexes with Luminescent Platinum(II) Complexes Bearing a Pendant Nucleobase

Abstract

Guanine quadruplexes are tetra‐stranded nucleic acid structures currently raising significant interest in the context of the development of potential anticancer therapeutics with a new mode of action. They are composed of planar guanine tetrads, allowing a high‐affinity targeting by using molecules with a large π surface. However, the extreme topological versatility of guanine quadruplexes impedes a straightforward targeting of particular preselected guanine‐rich sequences. We report here a systematic study of a family of luminescent platinum(II) complexes devised to overcome this challenge. By attaching a pendant adenine or thymine nucleobase as a substituent to one of the ligands at the platinum center, an additional recognition site is introduced with the aim of modulating the affinity of the metal complex to different DNA sequences. By comparing different attached nucleobases and a series of linker moieties, first conclusions are drawn with respect to the scope of this approach.

Monoanionic C^N^N Luminophores and Monodentate C-Donor Co-Ligands for Phosphorescent Pt(II) Complexes: A Case Study Involving Their Photophysics and Cytotoxicity

“…Notably, the pure cyanido complex (4) was not accessible by straight conversion of (1) with KCN or AgCN. Recently, the formation of (4) upon exchange of the chlorido ligand by pyridine and subsequent treatment with KCN was reported . Using a different approach, we report herein the synthesis of (4) via the reaction of an in situ generated Pt­(II) acetonitrile complex with KCN at 90 °C in a MeCN/MeOH 1:1 mixture (Scheme ).…”

“…Recently, the formation of (4) upon exchange of the chlorido ligand by pyridine and subsequent treatment with KCN was reported. 34 Using a different approach, we report herein the synthesis of (4) via the reaction of an in situ generated Pt(II) acetonitrile complex with KCN at 90 °C in a MeCN/MeOH 1:1 mixture (Scheme 1). In order to introduce an Nheterocyclic carbene co-ligand and to yield complex (6), a two-step reaction starting from (1) was performed (Scheme 1).…”

Thiazole orange-carboplatin triplex-forming oligonucleotide (TFO) combination probes enhance targeted DNA crosslinking

“…[7][8][9][10] These modern strategies target extended genomic tracts while overcoming shortcomings in the targeting limitations of small molecule platinum drugs. 11 Precise targeting is the key impact of this technology with platinum nucleic acid hybrids achieving effective gene-knockdown in vitro. 8 We recently reported the generation of azide-modified cis-platinum(II) complexes and showed how their copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) 'click chemistry' attachment to TFOs yielded effective platinum(II) nucleic acid hybrids (Fig.…”

Synthesis, Structure, and Photophysical Properties of Platinum(II) (N,C,N′) Pincer Complexes Derived from Purine Nucleobases

“…In this regard, platinum complexes bearing tridentate ligands have attracted particular interest, as they can bind to and intercalate DNA, trigger the formation of G-quadruplexes, , cause interstrand cross-links (ICL), and generate extensive conformational alterations . The luminescent properties associated with many of these complexes − have helped the study of interaction models , and have also been used to investigate intracellular processes in vivo. …”