A Cytotoxic Bis(1,2,3‐triazol‐5‐ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation

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.

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…In short, 266 was notably cytotoxic against the breast cancer cell line MDA-MB-231. 202 Liang et al synthesized a series of gold( iii )–N-heterocyclic thiosemicarbazone complexes 267a–e . The in vitro cytotoxicity of these gold( iii ) complexes was examined in the human malignant cell lines MGC-803, MCF-7, SK-N-MC, and HepG2, as well as in normal HL-7702 cells.…”

Gold-to-Boron Aryl Transfer from a T-Shaped Phosphine–Borane Gold(I) Complex

“…As a result, gold is 3-coordinate and sits in T-shaped geometry with P–Au–Cl and P–Au–B bond angles of 174.25(2) and 81.25(5)°, respectively. Rare precedents for T-shaped Au­(I) complexes derive from ambiphilic (Figure ) ,, or pincer LXL ligands . The Au–B distance in 2 is short at 2.555(2) Å.…”

Cancer molecular biology and strategies for the design of cytotoxic gold(i) and gold(iii) complexes: a tutorial review

“…The Au(III) ion of the sterically encumbered CNC pincer complex 33 is sufficiently stabilized by the bis-1,2,3-triazol-5ylidenes and the anionic carbazolide ligand scaffold against reduction by GSH. 280 Furthermore, 33 showed promising selectivity during in vitro cytotoxicity studies (entry 14, Table 3). Further mechanistic studies revealed that 33 binds to dsDNA via partial intercalation, while in silico experiments suggested that 33 might play a role in the stabilization of DNA 3WJs due to its charge (+1) and shape complementarity.…”

“…Further mechanistic studies revealed that 33 binds to dsDNA via partial intercalation, while in silico experiments suggested that 33 might play a role in the stabilization of DNA 3WJs due to its charge (+1) and shape complementarity. 280 Since the discovery that Au(III) can be stabilized for use in biological media and protected against reduction under physiological conditions by judicious choice of appropriate ligand scaffolds, many more examples have been reported and mechanistically explored for their antitumour potential. In particular, porphyrin-and CNC pincer-stabilized Au(III) complexes show exceptional promise, although selectivity towards cancer over healthy cells remains a challenge calling for future solutions.…”