A Click Chemistry Approach to Targeted DNA Crosslinking with cis-Platinum(II) Modified Triplex Forming Oligonucleotides.
Hennessy J., McGorman B., Molphy Z., Farrell NP., Singleton D., Brown T., Kellett A.
Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches therefore seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry-based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of Pt(II)-TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA intercalating fluorophore-into Pt(II)-TFOs constructs, enhanced target binding and discrimination between target and off -target sequences was achieved.