TY - JOUR
T1 - A Click Chemistry-Based Artificial Metallo-Nuclease
AU - Gibney, Alex
AU - de Paiva, Raphael E.F.
AU - Singh, Vandana
AU - Fox, Robert
AU - Thompson, Damien
AU - Hennessy, Joseph
AU - Slator, Creina
AU - McKenzie, Christine J.
AU - Johansson, Pegah
AU - McKee, Vickie
AU - Westerlund, Fredrik
AU - Kellett, Andrew
N1 - Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2023/9/18
Y1 - 2023/9/18
N2 - 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.
AB - 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.
KW - Click Chemistry
KW - Copper
KW - DNA Damage
KW - Nuclease
UR - http://www.scopus.com/inward/record.url?scp=85164206530&partnerID=8YFLogxK
U2 - 10.1002/anie.202305759
DO - 10.1002/anie.202305759
M3 - Article
C2 - 37338105
AN - SCOPUS:85164206530
SN - 1433-7851
VL - 62
SP - e202305759
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 38
M1 - e202305759
ER -