A Click Chemistry-Based Artificial Metallo-Nuclease
Journal article, 2023
Artificial metallo-nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3-triazole linker produced by the Cu-catalysed azide-alkyne cycloaddition (CuAAC) reaction can be directed to build Cu-binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl-thiophene to develop TC-Thio, a bioactive C3-symmetric ligand in which three thiophene-triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X-ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII-TC-Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide- and peroxide-dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.
Nuclease
Copper
Click Chemistry
DNA Damage
Author
Alex Gibney
Dublin City University
Raphael E.F. de Paiva
Dublin City University
Vandana Singh
Massachusetts Institute of Technology (MIT)
Chalmers, Life Sciences, Chemical Biology
Robert Fox
Dublin City University
Damien Thompson
University of Limerick
Joseph Hennessy
Dublin City University
Creina Slator
Dublin City University
C. J. McKenzie
University of Southern Denmark
Pegah Johansson
Sahlgrenska University Hospital
University of Gothenburg
Vickie McKee
Dublin City University
University of Southern Denmark
Fredrik Westerlund
Chalmers, Life Sciences, Chemical Biology
Andrew Kellett
Dublin City University
Angewandte Chemie - International Edition
1433-7851 (ISSN) 1521-3773 (eISSN)
Vol. 62 38 e202305759Subject Categories
Biochemistry and Molecular Biology
DOI
10.1002/anie.202305759