Gold Acyclic Diaminocarbene Complexes as Selective and Potent Agents for Multitarget Cancer Therapy

Abstract

Gold acyclic diaminocarbene (ADC) complexes represent a promising, yet underexplored, class of chemotherapeutics. ADCs offer superior flexibility and stronger sigma donation compared with traditional N-heterocyclic carbenes, making them ideal ligands for stable gold-based drugs. In this study, a series of gold ADC complexes were synthesized via the nucleophilic addition of amines to [AuCl(CNCy)], yielding three structural families: gold-chloride-ADC (chiral and achiral), bis(carbene), and thiolate-gold-ADC complexes. Extensive characterization, including X-ray diffraction, revealed noncovalent interactions, such as hydrogen bonding and aurophilic contacts, that significantly shape their molecular architecture. These complexes exhibit potent cytotoxicity (IC₅₀ in submicromolar) against drug-resistant cancer cell lines (A549, HCT116 WT, Jurkat, MiaPaca2), with some showing high selectivity toward cancer cells over healthy lymphocytes (selectivity index up to 74). Mechanistic investigations indicate that they disrupt mitochondrial function, elevate reactive oxygen species (ROS), and, in the case of bis(carbene) species, bind DNA. Apoptosis is induced at low concentrations, while higher doses trigger alternative death pathways. Notably, they also strongly inhibit thioredoxin reductase (TrxR), comparable in potency to auranofin. The combination of ROS induction, DNA interaction, mitochondrial disruption, and TrxR inhibition highlights the multitargeted anticancer potential of gold-ADC complexes and supports their further development as selective and effective chemotherapeutic agents.

Figure 1

Gold ADC complexes with antitumor properties.

Scheme 1. Synthesis of Gold(I) Acyclic Diaminocarbenes 1

Scheme 2. Synthesis of the Bis(carbene) Gold(I) Species 2

Scheme 3. Synthesis of the Thiolate-Gold(I)-ADC Complexes 3

Figure 2

Molecular structure of complex 1a (A) and association of molecules of 1a in dimers through aurophilic interactions (B).

Figure 3

Molecular structure of complex 1b.

Figure 4

Molecular structure of complex 3c (A) and association of molecules of 3c in pairs through hydrogen bonding (B).

Figure 5

Flow cytometry studies on complex 2a in Jurkat Vector and Jurkat shBak at 10 μM and 20 μM.

Figure 6

Flow cytometry studies on complex 2a in Jurkat and Jurkat + z-VAD-fmk at 10 μM and 20 μM.

Figure 7

Graphics for the flow cytometry studies on complex 2a at different concentrations: (a) Jurkat Vector and Jurkat shBak and (b) Jurkat and Jurkat + z-VAD-fmk.

Figure 8

ROS and ΔΨ of complex 3b in A549 cells.

Figure 9

Absorption spectral titration experiments for complexes 2a and 2b. The arrow indicates that the absorbance of the complex decreases with the addition of CT-DNA.

Figure 10

Insulin reduction assay.