A Cytotoxic Bis(1, 2, 3‐triazol‐5‐ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation. Issue 32 (17th May 2021)

• Record Type: Journal Article
• Authors: van der Westhuizen, Danielle; Slabber, Cathryn A.; Fernandes, Manuel A.; Joubert, Daniël F.; Kleinhans, George; van der Westhuizen, C. Johan; Stander, André; Munro, Orde Q.; Bezuidenhout, Daniela I.
• Is Part Of: Chemistry. Volume 27:Issue 32(2021)
• Page Start: 8295
• Page End: 8307
• Publication Date: 2021-05-17
• Subjects: anticancer -- cytotoxicity -- gold complexes -- mesoionic carbenes -- metallodrugs; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202100598
• Languages: English
• ISSNs: 0947-6539

Abstract

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) Au I ‐CNC pincer complex suitable for oxidation to the redox‐stable [Au III (CNC)Cl] + cation. Although the ligand salt and the [Au III (CNC)Cl] + complex were both notably cytotoxic toward the breast cancer cell line MDA‐MB‐231, the Au III complex was somewhat more selective. Electrophoresis, viscometry, UV‐vis, CD and LD spectroscopy suggest the cytotoxic [Au III (CNC)Cl] + complex behaves as a partial DNA intercalator. In silico screening indicated that the [Au III (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 Au III 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. Abstract : Towards new Au III anticancer agents . Herein a redox‐stabilised DNA‐targeting Au III bis(carbene) pincer complex with significant cytotoxicity is reported that is likely underpinned by partial DNA intercalation. In silico studies indicate that the complex can also target unusual DNA forms such as 3‐way junctions and Z ‐DNA. The structures of several multinuclear Ag I complexes discovered en route to the target Au III complex were also elucidated.