# N-Heterocyclic Carbene-Gold(I) Complexes Targeting Actin Polymerization
###### Abstract  
Transition metal complexes are attracting attention because of their various chemical and biological properties. In particular, the NHC-gold complexes represent a productive field of research in medicinal chemistry, mostly as anticancer tools, displaying a broad range of targets. In addition to the already known biological targets, recently, an important activity in the organization of the cell cytoskeleton was discovered. In this paper, we demonstrated that two NHC-gold complexes (namely **AuL4** and **AuL7**) possessing good anticancer activity and multi-target properties, as stated in our previous studies, play a major role in regulating the actin polymerization, by the means of in silico and in vitro assays. Using immunofluorescence and direct enzymatic assays, we proved that both the complexes inhibited the actin polymerization reaction without promoting the depolymerization of actin filaments. Our outcomes may contribute toward deepening the knowledge of NHC-gold complexes, with the objective of producing more effective and safer drugs for treating cancer diseases.  
NHC-gold complexes; actin; anticancer +
Footnote †: journal: NHC-gold  
because of its toxicity [6]. Instead, the literature shows many in vitro and in vivo studies conducted on the anticancer activities of another important gold-based complex, i.e., auranofin [(tetra-O-acetyl-\(\beta\)-D-glucopyranosyl)-thio] (triethylphosphine)-gold(I) (Figure 1), a second generation drug, which targets, in particular, the mitochondrial enzyme thioredoxin reductase (TrxR) [7]. These studies paved the way to the design, synthesis, and biological evaluation of many gold-based agents, mostly for the treatment of cancers. In this scenario, the gold complexes with N-heterocyclic carbene (NHC) ligands represent a challenging thread because of their ability to potently inhibit TrxR and decrease cancer cell proliferation [8; 9]. However, TrxR is not the only target of anticancer gold complexes reported on so far. Indeed, amongst the other important functions, DNA and related enzymatic machinery interference [10], mitochondrial damage (mostly for cationic gold(I) biscarbene complexes) [11; 12], and the inhibition of protein tyrosine phosphatases (PTP) [13] should also be noted. More recently, evidence indicated that NHC-gold complexes play an important role in regulating the cytoskeleton dynamics [14; 15; 16; 17; 18], interfering with the tubulin and/or actin metabolism. In our previous studies, we individuated two lead molecules, i.e., **AuL4** and **AuL7** (Figure 1) [15; 18], demonstrating that they are good anticancer compounds and possess different biological properties, including the ability to regulate the tubulin polymerization reaction in two different ways. Indeed, **AuL4** is able to stabilize the tubulin filaments, behaving as one of the most well-known drug, paclitaxel, whereas **AuL7** hampers the tubulin polymerization reaction, such as the vinblastine, one of the most used vinca alkaloids that induces the assembly of tubulin into non-microtubule polymers, such as para-crystals or spiral proto-filamentous structures [19]. In this paper, another important biological target of the above-mentioned NHC-gold complexes has been studied, namely the actin, using as references the molecules lattrunculin A (LA) and cytochalasin B (CB) (Figure 2). By using in silico and in vitro assays, we proved that both leads are able to inhibit the actin polymerization, with an efficacy similar to that of cytochalasin B (Phomin), a well-established cell-permeable fungal inhibitor of the actin polymerization. This evidence highlights, once again, the multi-target potential of the studied compounds, and is seminal for the development of potent and selective anticancer drugs targeting the actin, with negligible cytotoxic effects on the normal cells.  
Figure 1: Molecular structure of potassium dicyanoaurate, auranofin, cytochalasin B, lattrunculin A, **AuL4** and **AuL7**.