A Click Chemistry-Based Artificial Metallo-Nuclease

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 C-3-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 Cu-II and Cu-I complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, Cu-II-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.

de Paiva, R. E. F.Dublin City University (author)
Singh, Vandana,1985Massachusetts Institute of Technology (MIT),Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)vsingh (author)
Fox, R. (author)
Thompson, D.University Of Limerick (author)
Hennessy, J.Dublin City University (author)
Slator, C.Dublin City University (author)
McKenzie, C. J.Syddansk Universitet,University of Southern Denmark (author)
Johansson, Pegah,1978Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine,Sahlgrenska universitetssjukhuset,Sahlgrenska University Hospital,University of Gothenburg(Swepub:gu)xjopeg (author)
McKee, V.Dublin City University,Syddansk Universitet,University of Southern Denmark (author)
Westerlund, Fredrik,1978Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)fredrikw (author)
Kellett, A.Dublin City University (author)
Dublin City UniversityMassachusetts Institute of Technology (MIT) (creator_code:org_t)

By the author/editor: Gibney, A.; de Paiva, R. E. ...; Singh, Vandana, ...; Fox, R.; Thompson, D.; Hennessy, J.; show more...; Slator, C.; McKenzie, C. J.; Johansson, Pegah ...; McKee, V.; Westerlund, Fred ...; Kellett, A.; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

By the university: University of Gothenburg; Chalmers University of Technology

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