The synthesis and characterization of a redox-stable gold(III) bis(carbene) pincer complex, [AuIII(CNC)Cl]+, based on a modified bis(1,2,3-triazol-5-ylidene)carbazole ligand scaffold are reported. The complex was prepared by metalation of the N1,N3-diarylated triazolium salt L4 with AuI followed by oxidation using iodobenzene dichloride. X-ray crystallography confirmed a square planar geometry around the AuIII center, coordinated by two carbene carbon atoms and one amido nitrogen atom, with a chloride ligand occupying the final coordination site. The structural parameters—particularly the shortened Au–Namido bond (2.010 Å) and average Au–Ccarbene bond length (2.047 Å)—are consistent with the +3 oxidation state and reflect strong electronic stabilization provided by the CNC pincer scaffold.
The complex exhibits exceptional resistance to reduction by glutathione (GSH), a major intracellular reductant. 1H NMR analysis over 48 hours and two months in DMSO showed no significant changes, indicating no ligand dissociation or chloride exchange. Mass spectrometry detected a dicationic species at m/z = 722.3282, corresponding to either [4b – Cl + GSH]²⁺ or [4b-SG – Cl + H]²⁺, confirming the formation of a stable adduct rather than reduction to AuI. This remarkable redox stability is attributed to the combination of steric shielding by the bulky 2,6-diisopropylphenyl (Dipp) groups and strong σ-donation from the carbene ligands, which effectively protect the metal center from reductive degradation.
Cytotoxicity assays against the MDA-MB-231 breast cancer cell line revealed an IC50 value of 2.3 μM, while the non-tumorigenic EA.hy926 cell line exhibited an IC50 of 8.6 μM, yielding a therapeutic index (T.I.) of 3.8. These values fall within the range observed for other gold(III) complexes (IC50: 0.1–35 μM; T.I.: 2.5–147), indicating good selectivity. Notably, the free ligand precursor salt L4 displayed even greater potency (IC50 = 0.4 μM), suggesting that the triazolium ion may possess intrinsic biological activity independent of the metal center.
DNA interaction studies revealed a unique binding mode. UV-vis spectroscopy showed a pronounced hypochromic effect with increasing ctDNA concentration, accompanied by minor bathochromic shifts but no isosbestic points, indicating a complex, non-equilibrium binding process. A Hill fit yielded a binding constant KA = 3.7(3) × 10⁴ M⁻¹. Circular dichroism (CD) spectra exhibited a progressive shift from positive to negative intensity, confirming stable complex-DNA interaction.67469-78-7 Synonym The sigmoidal response at 207 nm gave KD = 3.9(5) μM (KA = 2.6(4) × 10⁵ M⁻¹), indicating high-affinity binding. Linear dichroism (LD) spectroscopy provided definitive evidence: the achiral complex developed strong negative LD signals upon DNA binding, with maxima at 305 and 294 nm and a sign reversal at 274 nm, confirming that the carbazole ring system is oriented perpendicular to the DNA helix axis—characteristic of intercalative binding.
Viscometry results were striking: a 60% increase in ctDNA viscosity was observed, significantly exceeding the 20% increase seen with ethidium bromide (EB). The sigmoidal saturation curve fits a single-step Hill isotherm, suggesting cooperative binding. This unprecedented viscosity increase cannot be explained by classical intercalation or groove binding and instead suggests a unique mechanism involving stabilization of higher-order DNA structures. Electrophoresis assays confirmed this: 4b caused dose-dependent retardation of supercoiled DNA and induced the formation of dimeric nicked-open circular forms, indicating intermolecular DNA–DNA interactions.28399-31-7 Formula
In silico docking simulations using Glide revealed that the complex preferentially targets DNA three-way junctions (3WJs) and Z-DNA over canonical B-DNA.PMID:30571007 In the 3WJ pocket, formed by the palindromic sequence 5′-d(CGTACG)-3′, the complex binds with excellent shape complementarity. Hydrophobic interactions between the carbazole and Dipp groups and adenine/thymine bases dominate, along with electrostatic attraction to the phosphate backbone. The carbazole ring intercalates into one of the central 5′-TA-3′ steps, effectively inserting a single-stranded segment into the triangular cavity. Docking scores ranged from 10.7 to 11.9 kcal/mol, indicating highly favorable thermodynamics. This ability to stabilize dynamic, non-canonical DNA structures may underlie the compound’s unique biophysical behavior and potent cytotoxicity.
In conclusion, the [AuIII(CNC)Cl]+ complex represents a significant advance in gold(III) metallodrug design. Its combination of redox stability, selective cytotoxicity, and dual targeting of both standard and non-canonical DNA structures makes it a promising candidate for anticancer therapy. The findings underscore the critical role of ligand architecture in enabling both chemical robustness and biological function, offering a blueprint for future development of next-generation DNA-targeting agents.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com