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

Joseph Hennessy; Piotr Klimkowski; Daniel Singleton; Alex Gibney; Malou Coche; Nicholas P Farrell; Afaf H El-Sagheer; Tom Brown; Andrew Kellett

doi:10.1039/d3md00548h

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

RSC Med Chem. 2023 Oct 31;15(2):485-491. doi: 10.1039/d3md00548h. eCollection 2024 Feb 21.

Authors

Affiliations

¹ SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, School of Chemical Sciences, Dublin City University Glasnevin Dublin 9 Ireland andrew.kellett@dcu.ie.
² Chemistry Research Laboratory, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK.
³ ATDBio Ltd., School of Chemistry, University of Southampton Southampton SO17 1BJ UK.
⁴ Department of Chemistry, Virginia Commonwealth University Richmond VA 23284-2006 USA.
⁵ School of Chemistry, University of Southampton Southampton SO17 1BJ UK.
⁶ Department of Science and Mathematics, Faculty of Petroleum and Mining, Engineering, Suez University Suez 43721 Egypt.

Abstract

We report a new class of carboplatin-TFO hybrid that incorporates a bifunctional alkyne-amine nucleobase monomer called AP-C3-dT that enables dual 'click' platinum(ii) drug conjugation and thiazole orange fluorophore coupling. Thiazole orange enhances the binding of Pt(ii)-TFO hybrids and provides an intrinsic method for monitoring triplex formation. These hybrid constructs possess increased stabilisation and crosslinking properties in comparison to earlier Pt(ii)-TFOs, and demonstrate sequence-specific binding at neutral pH.