In the context of chemotherapeutic drugs, platinum-based complexes have dominated the scene for decades, remaining among the most effective and employed treatments [1,2]. However, they present significant limitations, such as severe side effects, frequent occurrence of intrinsic or acquired resistance and the possibility of cancer relapse, especially for certain types of cancer [3,4]. In this frame, the scientific community has been spurred towards an intensive search for new anticancer metallodrugs based on different metal center, among which ruthenium, palladium and gold play an important role [1,[5], [6], [7], [8], [9], [10]]. Since the disclosing of cytotoxic properties of the antirheumatic drug auranofin (AF, Fig. 1), this compound and more in general the Au(I)-based compounds, have been extensively studied with the aim of finding better anticancer drugs with respect to the well-known platinum-based compounds [11,12]. Anyway, despite the promising preliminary results, auranofin has still not gained FDA approval for any neoplastic diseases; however, this spurred the interest of the bioinorganic chemists' community to work on more effective and selective gold-based compounds [13,14]. Among all the newly synthesized compounds, the phosphine‑gold(I) linear compounds represent a promising class endowed of an even better pharmacological profile with respect to auranofin itself, such as higher cytotoxicity and selectivity towards cancer cells [[15], [16], [17], [18]].

This approach involves the systematic modification of different portions of the auranofin structure, including the substitution of the phosphine moiety with other ligands [19], the functionalization with biologically relevant molecules [20], and the fine-tuning of the metal centre reactivity through the replacement of the thioglucosetetraacetate with different halides or pseudohalides [21,22]. These modifications can potentially result in new gold(I) complexes with enhanced cytotoxicity, improved pharmacokinetic properties, and reduced toxicity towards healthy cells [16]. The abundant literature on auranofin provides various information about the effects of small structural changes on its activity [15]. In 2017 some of us reported the synthesis of [AuI(PEt3)], an analogue of AF bearing an iodine atom in the place of thioglucose moiety [17,21]. In comparison with AF and [AuCl(PEt3)], [AuI(PEt3)] shows higher lipophilic properties and, interestingly, still a similar cytotoxic effect towards four CRC cell lines, with IC50 values falling in the nanomolar range and no cytotoxic activity on healthy cells (human fibroblast cell line and human embryonic kidney cells). These results highlight that the presence of the thiosugar moiety is not strictly correlated with the cytotoxic potential, being this latter almost exclusively attributable to the [Au(PEt3)]+ cation. Moreover, other works well show how tuning some relevant chemical properties, such as lipophilicity and water solubility, can be useful to improve bioavailability, and then the overall pharmacological activity. Indeed, the in vivo profile obtained for [AuI(PEt3)] on the murine model presents a considerable improvement with respect to AF [16]. Another example where the thioglucosetetraacetate ligand has been replaced, obtaining interesting differences in the activity, is AFETT ((ethylthiosalicylate(triethylphosphine)gold(I)) [20]. This latter compound has been designed taking inspiration from AF as well as the Hg-based complex thimerosal, replacing AF's thioglucosetetraacetate with an ethylthiosalicylate moiety. Compared to auranofin, AFETT features some peculiar and unique characteristics such as lower lipophilicity, higher water solubility and a prompter reactivity towards the investigated target biomolecules. Because of these differences, AFETT could exhibit considerable pharmaceutical and therapeutic advantages over auranofin itself [20]. Another strategy investigated by our group for designing new AF analogues involves the modification of phosphine ligand, which is part of the pharmacologically active [Au(PEt3)]+ fragment, as opposed to the thioglucosetetraacetate which mainly has a “functional” role [23]. For example, our research group recently reported the synthesis of a panel of AF's analogues in which triethylphosphine was replaced with a trimethylphosphite ligand, while the gold(I) linear coordination was completed with halide or thioglucose tetraacetate moiety [19]. All the newly synthesized compounds showed stability in aqueous solution, but significant differences with respect to auranofin were highlighted when interacting with some selected target proteins [19].

In the frame of the discussed modification strategies, we synthesized three new complexes where the triethylphosphine ligand of the promising [AuI(PEt3)] complex was replaced by triphenylphosphine, triphenylarsine and triphenylstibine (Fig. 2). The substitution of phosphorus with other atoms of the same group should lead to a different coordination bond strength and, hence, to a different reactivity of the entire molecule. Another appealing factor is the possible synergistic effect, which refers to the advantageous interaction of different therapeutic agents [24], obtained through the combined action of gold with As and Sb. More in detail, both arsenic and antimony present cytotoxic features in the anticancer therapies context, although only arsenic is currently used in the clinic for the treatment of relapsed acute promyelocytic leukaemia (APL) as arsenic trioxide [25,26]. Nevertheless, antimony is employed as an antiparasitic agent in the treatment of leishmaniasis [27,28].