Cancer is among the leading causes of death worldwide, with a devastating statistical rate of nearly ten million deaths in 2021 [1]. Prevention, early detection, and effective therapeutic treatment are the main weapons against this disease [1,2]. Cisplatin and its analogues, such as carboplatin and oxaliplatin, are widely used chemotherapeutic agents in the clinical treatment of various cancers, including testicular, breast, ovarian, head and neck, bladder, small and non-small cell lung cancers, etc. [3,4]. However, their effectiveness is limited due to resistance, high toxicity and severe side effects that are reported [3,[5], [6], [7]]. To achieve further progress in cancer control, the discovery and development of new chemotherapeutic agents with better efficacy and less toxicity than the clinically used platinum-based drugs is of great importance. To overcome the problems caused by platinum-containing drugs, many scientists have shifted their research to non‑platinum metal-based complexes [8,9].

Among non‑platinum potential chemotherapeutics, organotin(IV) compounds are considered one of the most promising, owing to their outstanding structural features and strong biological activity [10,11]. Previous screenings of organotin(IV) compounds for their therapeutical potential have shown that these compounds possess antimicrobial [12], antioxidant [13], antidiabetic [14], antileishmanial [15], schizonticidal [16], anti-hyperbilirubinemia [17], and antimalarial activity [18]. The biological activity of organotin(IV) complexes is essentially related to the number and type of organic substituents, and the nature of ligands bonded to the tin center [11,19]. In the past few years, the significant anticancer activity of many di- and triorganotin(IV) complexes has been identified. Some of these compounds exhibit similar or even better cytotoxic activity than clinically used cisplatin [12,17,20]. Other advantages of organotin(IV) complexes over clinically used platinum-based drugs include lower toxicity and induction of cell death at low doses, so the cells do not develop resistance [21]. Organotin(IV) compounds form relatively stable complexes with ligands containing O, N, S and P hetero donor atoms [16]. In terms of anticancer activity, organotin(IV) carboxylates usually exhibit the best cytotoxicity compared to organotin(IV) thiolates and dithiocarbamates [17]. It is generally adopted that diorganotin(IV) complexes show lower anticancer potential than their triorganotin(IV) analogues [22]. However, diorganotin(IV) complexes bearing maleimidopropanoate ligand, were reported to show anticancer activity more potent than cisplatin against A498 (renal cancer), EVSA-T (breast cancer), H226 (non-small cell lung cancer), IGROV (ovarian cancer), M19 (melanoma), MCF-7 (a mammary tumor) and WiDr (a colon carcinoma) cell lines [23]. According to the literature, there is a strong correlation between lipophilicity and cytotoxicity, and the most lipophilic compounds are the most cytotoxic [24]. Among the organotin(IV) complexes, the general pattern of lipophilicity is R3Sn+ > R2Sn2+ > RSn3+, with the triorganotin(IV) complexes showing the highest potency [25,26]. The nature of carboxylato ligand may play the key role in the controlling of bioactivity of organotin(IV) complexes, as some recent studies suggest the necessity of balance between lipophilicity and solubility of complexes for an effective interaction with possible target sites [27,28].

An interesting approach in designing of new anticancer drugs could be combining the lipophilic nature of the metal ion and biologically active ligands into a single molecular skeleton with a better pharmacological profile [24]. Quinolones and their derivatives have been the most extensively studied heterocyclic compounds, regarding their established biological activity [29,30], high bioavailability, low degree of binding to plasma proteins, and strong safety profile [31,32]. Many naturally plant-derived and synthetic quinolones have shown in vitro and in vivo anticancer activity, and few of them are currently used in clinical treatment or run under clinical trials (Vosaroxin, AT 3639) [[33], [34], [35]]. Quinolones represent an inspirative source in drug development, having scaffold privileged for the various structural modification at almost any position of the quinolone ring, providing compounds with different chemical and pharmacological properties [29]. Several studies reported syntheses and characterization of organotin(IV) complexes with fluoroquinolones as ligands [10,36,37]. However, their anticancer activity was not evaluated, and more studies need to unravel the structure–activity of the novel organotin(IV)-quinolone compounds as potential nonplatinum-based chemotherapeutic agents.

In addition to the high anticancer activity of organotin(IV) carboxylates and following the quote provided by the Nobel laureate that “the most fruitful basis for the discovery of a new drug is to start with old drug” [38], we decided to merge two biologically active compounds into one single molecular skeleton, providing thus drugs with better pharmacological profile, which could be considered as potentially new anticancer agents. For this paper, three novel diphenyltin(IV) complexes were synthesized and characterized by elemental microanalysis, FT-IR spectroscopy, and multi-nuclear (1H, 13C and 119Sn) NMR spectroscopy. Anticancer activity of newly synthesized complexes, 1–3, as well as ligand precursors, HL1–HL3, was determined against several tumor cell lines of human origin (breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT116), melanoma (A375)), and mouse (breast carcinoma (4T1), colon carcinoma (CT26), melanoma (B16)) using MTT and CV assays. Complex 1 was selected for mechanistic studies on HCT116 cells, thus caspase activity, apoptosis, proliferation and autophagy were assessed using flow cytometry. Furthermore, the production of the ROS/RNS species was determined by DHR staining.