A Click Chemistry Approach to Targeted DNA Crosslinking with <i>cis</i>‐Platinum(II)‐Modified Triplex‐Forming Oligonucleotides
Joseph Hennessy, Bríonna McGorman, Zara Molphy, Nicholas P. Farrell, Daniel Singleton, Tom Brown, Andrew Kellett
Abstract
Abstract 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.