Exploring the Reactivity and Biological Effects of Heteroleptic N‐Heterocyclic Carbene Gold(I)‐Alkynyl Complexes

Jens Oberkofler,James Platts,Alexander Pöthig,Brech Aikman,Fritz E Kühn,Riccardo Bonsignore,Angela Casini

doi:10.1002/ejic.201901043

Jens Oberkofler, James Platts + Show 5 more

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https://doi.org/10.1002/ejic.201901043

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Abstract

With the aim to explore the effects of different organometallic ligands on the reactivity and biological properties of a series of twelve heteroleptic AuI complexes, of general formula [Au(NHC)(alkynyl)] (NHC = benzimidazolylidene or 1,3‐dihydroimidazolylidene) were synthesized and characterized by 1H and 13C NMR and elemental analysis, and in some cases also by X‐ray diffraction. The compounds were all stable in H2O/DMSO as established by NMR spectroscopy, while they could react with model thiols (EtSH) in the presence of water to undergo ligand‐substitution reactions. 1H NMR experiments showed that dissociation of the more labile alkynyl ligand was possible for all compounds, while in the case of the benzimidazolylidene series also dissociation of the NHC ligand could be observed. DFT calculations suggest that, depending on the steric hindrance exerted by both the NHC wingtip groups and the alkynyl substituents, the reaction can proceed either via a π‐stabilized intermediate or with the alkynyl ligand remaining purely σ‐coordinated to the AuI center until completely dissociated. The most stable compounds in PBS buffer (pH 7.4), as assessed by UV‐Visible spectrophotometry, were further investigated for their ability to stabilize G4 DNA by FRET DNA melting assay, showing only moderate activity. Moreover, two derivatives were tested in vitro for their anticancer activities in three different human cancer cell lines and showed cytotoxicity in the low micromolar range.

Highlights

As the World Health Organization states in its report, approximately 14 million new cases of cancer and 8 million cancerrelated deaths were registered in the year 2012 alone, both numbers rising steadily and underpinning the urgency of development and improvement of new anticancer drugs.[1]
While AuI complexes generally feature a linear geometry, with the gold center coordinated by two ligands, AuIII compounds prefer a square-planar coordination and are isoelectronic (d8) to the aforementioned PtII compounds.[4]
Stability studies show that all compounds are stable in a mixture DMSO/H2O as evidenced by 1H NMR spectroscopy, but react in the presence of EtSH, leading in most cases, with the exception of compound 1, to the nucleophilic substitution of the alkynyl ligand by the thiol group (Step I)

Summary

Introduction

As the World Health Organization states in its report, approximately 14 million new cases of cancer and 8 million cancerrelated deaths were registered in the year 2012 alone, both numbers rising steadily and underpinning the urgency of development and improvement of new anticancer drugs.[1]. These variations are attributed to the formation of the NHC-AuI-SEt adduct (Scheme 2), and are in line with previous studies on the reactivity of Au NHCs with model thiols.[16,24] Instead, complex 1 behaves differently and undergoes the loss of the BzImi ligand already after 5 h (Figure S37).

Results

Conclusion