University of Oulu

D. van der Westhuizen, C. A. Slabber, M. A. Fernandes, D. F. Joubert, G. Kleinhans, C. J. van der Westhuizen, A. Stander, O. Q. Munro, D. I. Bezuidenhout, Chem. Eur. J. 2021, 27, 8295. https://doi.org/10.1002/chem.202100598

A cytotoxic bis(1,2,3-triazol-5-ylidene)carbazolide gold(III) complex targets DNA by partial intercalation

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Author: van der Westhuizen, Danielle1; Slabber, Cathryn A.1; Fernandes, Manuel A.1;
Organizations: 1Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, 2050 Johannesburg, South Africa
2Department of Physiology, University of Pretoria, 0031 Pretoria, South Africa
3Chemistry Department, University of Pretoria, 0028 Pretoria, South Africa
4Future Production: Chemicals, Pharmaceutical Technologies Research Group, Council for Scientific and Industrial Research (CSIR), 0184 Pretoria, South Africa
5Laboratory of Inorganic Chemistry, Environmental and Chemical Engineering, University of Oulu, 3000 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021062940471
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-06-29
Description:

Abstract

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI-CNC pincer complex suitable for oxidation to the redox-stable [AuIII(CNC)Cl]⁺ cation. Although the ligand salt and the [AuIII(CNC)Cl]⁺ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [AuIII(CNC)Cl]⁺ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII(CNC)Cl]⁺ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.

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Series: Chemistry. A European journal
ISSN: 0947-6539
ISSN-E: 1521-3765
ISSN-L: 0947-6539
Volume: 27
Issue: 32
Pages: 8295 - 8307
DOI: 10.1002/chem.202100598
OADOI: https://oadoi.org/10.1002/chem.202100598
Type of Publication: A1 Journal article – refereed
Field of Science: 116 Chemical sciences
Subjects:
Funding: The authors gratefully acknowledge the National Research Foundation, South Africa (NRF 105740, NRF 105529, and NRF 108521, DvdW, DIB). Part of this work is based on research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant No 64799, OQM). CJvdW acknowledges the Centre for High Performance Computing (CHPC), South Africa, for providing computational resources.
Copyright information: © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/