Transition metal complexes offer significant pharmacological advantages over conventional drugs, prompting extensive research into metal-ligand combinations to create anticancer metallodrugs beyond the clinically-used platinum compounds [[1], [2], [3], [4], [5]]. In this context, iron is a particularly attractive option being an endogenous element, fulfilling vital functions in the oxidation states + II and +III, and demonstrating relatively low toxicity in various forms [[6], [7], [8]]. A variety of iron complexes have been explored for their antitumor potential, with organometallic complexes featuring the robust iron-cyclopentadienyl moiety showing promise [[9], [10], [11], [12]]. Specifically, ferrocene derivatives have been extensively investigated, displaying a general ability to induce cancer cell death by undergoing intracellular FeII to FeIII oxidation, thereby disrupting cell redox homeostasis through the production of reactive oxygen species (ROS) [12,13]. Also iron(III) ferrocenium salts, the oxidized form of ferrocene, aroused a significant interest in the 1980s but these studies were subsequently abandoned [12,14]. Piano-stool iron(II) cyclopentadienyl complexes offer increased ligand variability, and several of them have been evaluated as anticancer agents [[15], [16], [17], [18]].

Since 2019, our efforts have concentrated on dinuclear complexes featuring nonendogenous iron(I) centers, derived from the commercially available [Fe2Cp2(CO)4]. In general, bimetallic scaffolds enable cooperative effects [[19], [20], [21], [22]], and particularly [Fe2Cp2(CO)4] allows for reactivity patterns unattainable on monoiron cyclopentadienyl compounds [[23], [24], [25], [26]]. This approach facilitates the construction of bridging cationic hydrocarbyl ligands with wide structural variability. The net cationic charge balances amphiphilicity and typically provides satisfactory water solubility [27], both of which are key prerequisites for drug development [[28], [29], [30]]. Following a screening study on numerous diiron bis-cyclopentadienyl carbonyl derivatives featuring a bridging hetero-carbyne ligand [27,31], we have identified two compounds warranting advanced studies, i.e. FETPY [32] and FEACYP [33] (Scheme 1A). When administered in vivo against murine carcinomas in a therapeutic regime, both FETPY and FEACYP revealed a strong ability to suppress tumor growth, with negligible toxicity.

A second-generation class of anticancer diiron species can be obtained from the coupling of aminocarbyne ligands, CN(R)Me, with alkynes (Scheme 1B). When terminal alkynes are involved (R'' = H), this reaction is regioselective and exhibits broad applicability, providing access to a potentially unlimited family of vinyliminium complexes (structure 1 in Scheme 1) [[34], [35], [36], [37]]. To date, more than 150 compounds of this type have been reported, and over 60 of them have been preliminarily evaluated for their antitumor potential on a restricted panel of cancer cell lines. These studies predominantly involved ovarian cancer cell lines (A2780 and its cisplatin-resistant variant A2780cisR), showing variable cytotoxicity depending on the vinyliminium substituents (R, R′, R″).

Notably, a useful strategy to improve the antitumor efficacy of metal compounds involves incorporating organic groups with recognized biological activities [[38], [39], [40], [41]]. This approach has proven successful across various metal structures. While chemically linked, the two components are expected to exert distinct functions within the tumor environment, potentially working synergistically to target multiple pathways [42].

Sulfur has been described as a "redox-chameleon" within biological systems, due to its ability to exist in up to ten different oxidation states, contributing to a complex network of sulfur-based redox reactions [43]. Several naturally-occurring organo-sulfur compounds are known to exhibit diverse biological activities, including anticancer properties and preventive effects [[44], [45], [46]]. For instance, the allyl-sulfide motif has served as an inspiration for the synthesis of various organic compounds designed as anticancer agents [[47], [48], [49]].

In this study, we present the synthesis and extensive evaluation of the anticancer potential of a series of diiron vinyliminium complexes incorporating sulfide functions. The selected vinyliminium framework (except for one case) comprises a cyclohexyl moiety (Cy), which has been shown to enhance the anticancer activity of metal complexes (including FEACYP) by facilitating their cellular uptake [37,50].