Anticancer drugs based on metal complexes of 2-imine-8-hydroxyquinolines

1 Introduction

Cancer remains one of the world’s leading causes of mortality, with over 19 million new cases and around 10 million deaths reported annually, according to GLOBOCAN 2022 (Ferlay et al., 2024). Despite significant advances in cancer therapies, current treatment regimens and particularly chemotherapy, are limited by issues such as drug resistance and systemic toxicity, as well as a lack of tumor selectivity. These challenges have driven the search for more effective and selective novel therapeutic agents, with metal-based complexes emerging as a promising alternative to organic and platinum-based drugs.

Among the various organic scaffolds explored in medicinal chemistry, 8-hydroxyquinoline (8HQ) has attracted widespread attention due to its diverse biological activities, including antibacterial, antiviral, antifungal, antineurodegenerative, and anticancer properties (Prachayasittikul et al., 2013; Gupta et al., 2021; Oliveri and Vecchio, 2016). 8-Hydroxyquinoline is characterized by a planar double aromatic ring system, consisting of a phenol fused with a pyridine. The position of the donor atoms gives the molecule strong metal-chelating properties, making it an ideal ligand for forming stable complexes with various metal ions (Gupta et al., 2021; Oliveri and Vecchio, 2016; Chan et al., 2013; Ding and Lind, 2009). The anticancer potential of 8HQ and its metal complexes is significant, and has been shown to be exerted by different pathways. Given its chelating ability, 8HQ can facilitate metal transport inside cells. It can also influence key biological processes such as the generation of reactive oxygen species (ROS), that may induce oxidative stress in cancer cells; by binding to DNA and interfering with replication and transcription; or by inhibiting critical enzymes for cancer cell (Pape et al., 2018; Barilli et al., 2014).

Modifications to the 8HQ scaffold, particularly at position 2 (adjacent to the nitrogen atom), have enabled the synthesis of derivatives with improved pharmacokinetic and pharmacodynamic profiles. One example is the 8-hydroxyquinoline-2-carboxaldehyde thiosemicarbazide copper complex (Zhang et al., 2008) that showed strong anticancer activity against cisplatin-resistant neuroblastoma and prostate cancer cells. Its mechanism of action involves generating ROS and cleaving DNA, ultimately leading to apoptosis. The same authors recently reported significant tumor size reduction in vivo using the complex in mice implanted with Luc-PC3 prostate cancer cells (Xie et al., 2018). A Cu(II)-8HQ-hydrazine complex has also been reported to cause cell cycle arrest in the S phase and disrupt the mitochondrial membrane potential, triggering apoptosis in MGC80-3 human gastric cancer cells (Yang et al., 2018).

Zinc plays a crucial role in cellular metabolism and apoptosis, acting as both a regulator and a protective agent in a variety of biological processes. It is essential for maintaining cellular homeostasis and is involved in disease prevention and therapy (Costa et al., 2023). Zn(II)-8HQ complexes containing 1,10-phenantholine derivatives have shown selectivity towards cancer cells while sparing normal cells, offering a promising therapeutic window. Studies have demonstrated their efficacy in inhibiting tumor growth in human cisplatin-resistant SK-OV-3/DDP ovarian cancer (SK-OV-3CR) cells, while reducing systemic toxicity to normal hepatocytes, compared to traditional chemotherapy (Du et al., 2023).

Vanadium compounds have also shown potential in cancer treatment due to their ability to interfere with cellular processes crucial for tumor growth and metastasis (Pessoa et al., 2015; Kioseoglou et al., 2015; Amante et al., 2021). Vanadium complexes bearing 8-hydroxyquinoline-based ligands have shown antiproliferative effects on cancer cells. They are more cytotoxic than cisplatin in A2780 cells, while displaying low cytotoxicity in primary fibroblasts. However, introducing substituents into the 8-hydroxyquinoline backbone reduced the antiproliferative effect of the vanadium complexes (Choroba et al., 2020). Nickel 8-HQ complexes have also been explored in this context, albeit to a lesser extent, with some showing cytostatic effects on HeLa cervical cancer cells (Barilli et al., 2014).

These studies emphasize the versatility of 8HQ as a ligand scaffold for complexes with different metal ions. 8-Hydroxyquinoline compounds offer a potential approach to cancer treatment, targeting multiple pathways while allowing for significant structural variation and optimization. However, key challenges remain, including issues of aqueous solubility, selectivity for cancer cells, and potential off-target effects. Innovative strategies such as ligand modification and advanced drug delivery systems (e.g., liposomal encapsulation) are essential to overcome these issues and translate these compounds into viable clinical options.

This mini-review summarizes the findings of a research project which aimed to develop new 8HQ-imine derived metal complexes, focusing on derivatives substituted at position 2. The compounds were fully characterized at the molecular level, and screened in vitro for their antiproliferative properties against several cell lines, as well as for their mechanisms of action. Selected compounds were encapsulated in nanoliposomes and evaluated in vivo for the treatment of malignant melanoma and colon cancer, demonstrating a significant reduction in tumor growth and size.

2 Chemistry of 8-hydroxyquinoline derivatives

8-Hydroxyquinoline is known for its high chelating ability, forming stable complexes with various metal ions (Choroba et al., 2020; Sgarlata et al., 2018; Scalese et al., 2022; Garribba et al., 2003; Abeydeera et al., 2023; Grice et al., 2018). Modifications at position 2, lead to derivatives with enhanced binding properties (Prachayasittikul et al., 2013). Three ligand families were developed (Figure 1) via condensation reactions with 2-carbaldehyde-8-hydroxyquinoline: Schiff bases–C=N (L ^**1-5**), (Côrte-Rea et al., 2023; Côrte-Real et al., 2024), hydrazones–C=N-NH (L ^**6**), (Ribeiro et al., 2022a; Ribeiro et al., 2022b), and hydrazide-hydrazones–C=N-NH-C=O (L ^**7-14**) (Ribeiro et al., 2022c; Ribeiro et al., 2023). Solution studies and spectrophotometric titrations revealed that all ligands were lipophilic and neutral at physiological pH. They were reacted with Cu(II), Zn(II), V(IV)O, Fe(III), Ni(II) and Ru(II) salts in order to explore their metal complexes, and expand their biological activity.

Schiff base ligands L ^**1-3** containing morpholine and piperidine N-heterocycles were reacted with Cu(II), Zn(II), (Côrte-Rea et al., 2023), V(IV)O, Ni(II) and Fe(III) ions to form 2:1 (L:M) metal complexes. Most of these complexes were characterized using single-crystal X-ray diffraction (SC-XRD), which revealed distinct coordination geometries. Overall, the Cu(II) species formed square planar complexes and square pyramidal dimers. V(IV)O acquired the expected square pyramidal geometry, whereas the Zn(II) and Ni(II) complexes formed octahedral geometries. The binding modes of the two 8HQ-2-imines differed, with a cis arrangement of the phenolate oxygen atoms for Zn(II) and Ni(II), and a trans arrangement for Cu(II) and V(IV)O. The ligands behaved as either tridentate (O_phenolate, N_quinoline and N_imine donors) or bidentate (O_phenolate and N_quinoline). Cu(II) complexes formed square planar complexes (N_quinoline and O_phenolate donors), and in two of these complexes, the oxygen atom acts as a bridging atom between Cu centers in dimeric structures. The ligands in the Zn(II) complexes are tridentate (O_phenolate, N_quinoline and N_imine), in a distorted octahedral geometry, with the phenolate oxygens in a cis arrangement relative to each other. No crystal elucidation was obtained for the Fe(III) complexes, but solution magnetic susceptibility measurements were consistent with a high-spin d⁵ configuration (S = 5/2 with five unpaired electrons in an octahedral environment).

Spectrophotometric titrations disclosed that the Cu(II) complexes exhibit higher thermodynamic stability than the Zn(II) complexes. However, when compared with 8-hydroxyquinoline, the Cu complexes lost stability, while the Zn complexes gained stability, in line with the respective bidentate and tridentate binding modes.

Schiff bases L ^**4-5** containing imidazole derivatives, were only complexed with Zn(II) (Côrte-Real et al., 2024). SC-XRD analysis of the Zn(II) complex with the imidazole derivative, [Zn(L ^**1** ) _**2** ] _***n*** revealed a one-dimensional polymeric chain structure consisting of alternating Zn(II) cations and bridging Schiff base ligands, in which the N-imidazole acts as a bridging atom. DFT calculations indicated that these ligands could exhibit dynamic behavior by adopting bi- and tridentate coordination in solution.

The benzothiazole-derived hydrazone ligand (L ^**6**), was found to form 1:1 and 2:1 (L:M) complexes with Zn(II) (Ribeiro et al., 2022a). Analytical and spectroscopic studies (NMR, FTIR, and UV-Vis) revealed the following binding modes: tetradentate in [ZnL(AcO)] (where AcO represents acetate) and bidentate in [ZnL₂]. This ligand was also complexed with other metal ions (V, Cu, Fe, Ru and Ni) (Ribeiro et al., 2022b) and different binding modes were proposed for each metal species. This demonstrates the ligand’s coordination versatility, as it can bind in bi-, tri- and tetradentate modes. The ligand and its metal complexes exhibited high lipophilicity.

Hydrazine-hydrazone ligands (L ^**7-14**) were synthesized from benzhydrazide with different para-substituted groups (R = H, Cl, F, CH₃, OCH₃, OH and NH₂). These ligands were used to study the interaction with Cu(II) and V(IV)O metal ions (Ribeiro et al., 2022c; Ribeiro et al., 2023). SC-XRD analysis of the OCH₃ derived (L ^**11**) Cu(II) complex revealed a trinuclear formula, which was proposed for all other Cu-complexes (Ribeiro et al., 2023). Solution studies indicated that neutral [Cu(L)] species predominate at physiological pH and cyclic voltammetry analysis determined the formal redox potentials to be between +377 and +395 mV vs. NHE (Normal Hydrogen Electrode).

Oxidovanadium(IV) complexes of these hydrazide-hydrazones were also synthesized (Ribeiro et al., 2022c), with spectrophotometric analysis confirming 1:1 and 2:1 L:M stoichiometries. Spectrophotometric and EPR (electron paramagnetic resonance) spectroscopy corroborated the presence of [VO(HL)₂], as the predominant species in a physiological environment.

These studies highlight the versatility of 8HQ derivatives in forming stable complexes, with various metal ions and different geometries, including square planar, square pyramidal, and octahedral structures, as well as monomeric, dimeric and polymeric forms. Modifications at C2 and the introduction of different functional groups can significantly influence the chelating properties, enhancing the solubility and stability, both of which are fundamental for therapeutic applications.

3 Anticancer activity

One of the aims of this research was to evaluate the anticancer potential of 2-imine-8HQ complex-based metallodrugs. Therefore, in vitro studies were conducted on multiple cancer cell lines, with a particular focus on melanoma (A375), lung adenocarcinoma (A549), and colon cancer (HCT-116).

In all in vitro cell studies, the cytotoxicity of the ligands was compared with that of the metal complexes and positive controls [the clinically used drugs, cisplatin and 5-fluorouracil (5-FU)]. Table 1 presents the IC₅₀ values for the compounds; however, direct comparisons are limited due to variations in the incubation period and the types of cell death assays employed in the evaluation (Côrte-Rea et al., 2023; Côrte-Real et al., 2024; Ribeiro et al., 2022a; Ribeiro et al., 2022b; Ribeiro et al., 2022c; Ribeiro et al., 2023).

TABLE 1. IC₅₀ values (in μM) after 48 h or 78 h of incubation, measured with the MTT or Sulforhodamine B assay (or other assay–check footnote).

CellTiter-Glo 3D kit (Promega).

As previously reported for 8-hydroxyquionoline (Gaál et al., 2018), the developed 8HQ ligands are cytotoxic to A375 melanoma cells, regardless of the assay used to measure the cytotoxicity and the incubation time, which were different in the different systems. Hydrazide-hydrazones L ^**7**, L ^**13** and L ^**14**, show an IC₅₀ < 15 μM in this cell line. Their metal complexes, with both Cu(II) and V(IV)O, are more cytotoxic than the ligands, with the copper complexes performing better than the vanadium complexes overall. The most effective compounds were VO(L ^**9** ) _**2**, Cu(L ^**7** )(AcO), Cu(L ^**10** ) and Cu(L ^**14** ). Although no structure-activity relationships could be established, the presence of electronegative elements such as fluorine (F) and nitrogen (N_py) increased cytotoxicity.

A549 cells, which are derived from human lung adenocarcinoma and are highly resistant to chemotherapeutic agents such as cisplatin (IC₅₀ = 17 ± 3 μM) are commonly used in cancer research due to the high mortality rate associated with this cancer type (Ribeiro et al., 2022c). Ligands L ^**7** -L ^**14** exhibited no cytotoxicity against A549 cells (except L ^**13**), and the V-complexes demonstrated limited efficacy with the lowest IC₅₀ values of 20.1 ± 0.1 μM) (Ribeiro et al., 2022c). In contrast, the Cu-complexes displayed significantly higher activity with IC₅₀ values lower than that of cisplatin, in the low micromolar range. The best compounds were the same as those observed against A375 cells (Ribeiro et al., 2023).

Copper and zinc complexes derived from Schiff bases L ^**1-3** were tested against a malignant melanoma cell line (A375) and a non-tumorigenic keratinocyte (HaCaT) cell line. Once again, the metal complexes exhibited higher cytotoxicity than the ligands (Côrte-Real et al., 2023), with the Cu(II) complexes demonstrating greater potency than the Zn ones. The Zn(II) complexes displayed some degree of selectivity towards melanoma cells, though their therapeutic index was limited (SI = 2.8) and the assays used in both cell lines were different. The V(IV)O, Ni(II) and Fe(III) complexes of L ^**2**, were also tested in A375 cells, with the best results being obtained with vanadium [IC₅₀(V) < IC₅₀(Ni) IC₅₀(Fe)] (Lopes et al., 2025).

The cytotoxicity of Schiff base Zn(II) complexes containing imidazole derivatives (L ^**4,5**) was evaluated across multiple cancer cell lines (Côrte-Real et al., 2024). These complexes displayed high cytotoxicity, comparable to that of cisplatin. More importantly, they exhibited no toxicity towards normal retinal pigment epithelial (RPE-1) cells, suggesting a promising safety profile.

The cytotoxic effects of the Zn(II) complexes with the hydrazone L ^**6** were evaluated in CT-26 and HCT-116 colon cancer cells, as well as in HaCaT normal cells (Ribeiro et al., 2022b). Obtained IC₅₀ values were in the low micromolar range, but selectivity was low. The Ni(II) and Ru(II) complexes also exhibited significant anticancer activity against colon cancer cells (Ribeiro et al., 2022b). Also, this ligand was more cytotoxic than its metal complex, but this was the only family in which this behavior was observed.

In summary, 8HQ metal complexes demonstrated strong cytotoxic activity, often surpassing the clinically used drugs, cisplatin and 5-fluorouracil (5-FU), despite generally displaying low selectivity. This drawback must be addressed to exploit the complexes’ high activity. While metal complexes have numerous advantages over organic molecules due to their different coordination modes, structures, charges, substitution reactions and redox properties, understanding the mechanisms by which they cause cell death is crucial to fully exploiting them.

4 Mechanistic insights

Aiming to evaluate the mode of cell beath different compound series were evaluated using different mechanistic assays, which reflect variations in project timelines and research questions.

From the L ^**1-3** Schiff bases (Côrte-Rea et al., 2023), Zn- and Cu-complexes of L ^**2** were selected, and cell death was assessed by flow cytometry in melanoma A375 cells, which showed that apoptosis was involved in the mode of cell death.

For the Zn(II) imidazole SBs, L ^**4-5**, A375 and triple-negative breast MDA-MB-231 cancer cells were selected for the mechanistic studies (Côrte-Real et al., 2024). Acridine orange and ethidium bromide staining confirmed nuclear condensation and the formation of apoptotic bodies. The results of the Annexin-V staining and the caspase 3/7 activation assays demonstrated that the breast cancer MDA-MB-231 cells exhibited a stronger response to apoptosis in comparison to the melanoma A375 cells. This finding suggests the presence of a dual mechanism involving both apoptosis and cell cycle arrest. Furthermore, both complexes effectively increased ROS levels, with higher levels observed in MDA-MB-231 cells compared to A375 cells. The presence of DNA double-strand breaks was detected, likely resulting from the generation of reactive oxygen species (ROS). Given that Zn(II) is not redox active, the generation of ROS may be attributable to mitochondrial dysfunction, inhibition of antioxidant enzymes, or activation of pro-oxidant enzymes. However, these hypotheses remain to be evaluated.

The investigation into the mechanism of action of the Ni(II) and Ru(II) complexes of L ^**6** was conducted through a series of assays. These assays revealed that the complexes induced cell cycle arrest, apoptosis, and migration inhibition in human (HCT-116) and murine (CT-26) colon cancer cells (Ribeiro et al., 2022b). The Ni-complex induced cell cycle arrest in the S phase in murine colon cancer cells, while the Ru-complex induced S phase arrest in both cell lines. The migration assays revealed a reduction in migration in HCT-116 cells by both Ni and Ru complexes (Ribeiro et al., 2022b). The toxicity mechanism of the Zn(II) complex [Zn(L ^**6** )(AcO)] was also investigated in both cell lines (Ribeiro et al., 2022a). Flow cytometry analysis demonstrated induced necrosis in CT-26 cells. The cell cycle analysis indicated that the Zn-complex exerts its antiproliferative effects through cell-cycle-independent mechanisms.

The hydrazine-hydrazone oxidovanadium (IV) complexes were evaluated in both melanoma and lung cancer cell lines (Ribeiro et al., 2022c). The Annexin V and 7-AAD staining revealed apoptosis induction in A375 cells, with the fluor substituted complex (VO(L ^**9** ) _**2**) being the most effective. In contrast, A549 cells demonstrated resistance to the majority of complexes, with the exception of VO(L ^**9** ) _**2**, which induced apoptosis with a greater efficacy than that of cisplatin. Caspase-3/7 activity assays confirmed that apoptosis was the primary mode of cell death. Subsequent analysis demonstrated elevated levels of ROS, which resulted in DNA damage, as indicated by the presence of double-strand breaks. The results of this study indicate that the metal complexes, particularly compound VO(L ^**9** ) _**2**, induce apoptosis through the generation of ROS and subsequent DNA damage.

With Cu(II) only selected compounds were evaluated: Cu(L ^**7** )(AcO), Cu(L ^**9** ), Cu(L ^**11** )(AcO) and Cu(L ^**14** ) (Ribeiro et al., 2023). Dihydroethidium staining revealed elevated levels of ROS in melanoma A375 cells, which were comparable to, or exceeded, the levels induced by cisplatin. In A549 cells, the induction of ROS was found to be generally milder, with the exception of complex Cu(L ^**14** ), which produced a significant increase. The addition of the antioxidant N-acetyl-cysteine significantly reduced the cellular toxicity of most complexes in both cell lines, thereby supporting their effects as being ROS-dependent. Further analysis, employing the technique of γH2AX staining, revealed that most complexes induced a significant degree of DNA damage in A375 cells. Complex Cu(L ^**7** )(AcO), with the unsubstituted ligand, caused notable DNA damage despite lower ROS induction, suggesting DNA damage through ROS-independent mechanisms. Annexin V staining and caspase 3/7 activation were used to demonstrate that all complexes, with the exception of Cu(L ^**11** )(AcO), effectively induced apoptosis in A375 cells, thus surpassing the efficacy of cisplatin. It was also demonstrated that Complex Cu(L ^**14** ), in containing the pyridinic nitrogen, was particularly potent.

These mechanistic studies, despite limited, provide a comprehensive understanding of the mechanisms underlying the anticancer activity of these metal-8HQ compounds. With Cu and V complexes, the processes involve the generation of ROS, the induction of DNA damage, and the subsequent induction of apoptosis, although this is not necessarily achieved through cell cycle arrest. For all other studied complexes (except [Zn(L ^**6** )(AcO)]) apoptosis is the mode of cell death.

5 Liposomal formulations and in vivo efficacy

Overall, the cell-based studies indicate high cytotoxicity for the complexes towards several cancer cells, but the major problem to overcome is cancer cell selectivity. The utilization of drug passive delivery, that takes advantage of the enhanced permeation and retention (EPR) effect, constitutes a viable strategy for achieving this objective. As with other macromolecules, nanoliposomes have the capacity to accumulate in areas of enhanced vascular permeability, such as inflammatory and tumor sites, which typically demonstrate a defective vascular system (Golombek et al., 2018). Exploring this effect requires prolonged drug circulation in the bloodstream, which can be achieved by incorporating polyethylene glycol (PEG) into the lipid composition. Tumor microenvironments are distinguished by their slightly acidic pH values, typically 6, in contrast to the “neutral” pH of 7.4 found in healthy tissues. The process of engineering liposomes for the purpose of pH-sensitive compound release is a relatively straightforward one. This can be achieved by incorporating pH-responsive phospholipids, such as dioleoyl phosphatidyl ethanolamine (DOPE) and cholesteryl hemisuccinate (CHEMS) (Allen and Cullis, 2013; Bulbake et al., 2017; Crommelin et al., 2020).

For the in vivo studies, the criteria for the selection were not simply the lowest IC₅₀ values, since often this does not translate into higher in vivo efficacy, but involved also the highest liposomal incorporation efficiency. As an example: although Zn(L ^**6** ) _**2** has lower IC₅₀ value than Zn(L ^**6** )(AcO) in HCT-116 cells its higher molecular mass makes its incorporation efficiency into the selected liposomes much lower. Also, these studies were carried out at different periods of time and some promising compounds were not yet studied. Following the identification of the optimal compound from two series for incorporation into the nanoliposomes, this strategy was applied to enhance the bioavailability and selectivity of 8HQ Zn-complexes of L ^**6** (Ribeiro et al., 2022a), and the Cu(II)-complex of L ^**2** (Coelho et al., 2025). After optimization of the encapsulation conditions for the complexes in liposomes, it was demonstrated that the liposomal formulations retained the antiproliferative activity of the free [Zn(L ^**6** )(AcO)] complex against murine and human colon cancer cell lines and Cu(L ^**2** ) _**2** against malignant melanoma cells.

The therapeutic potential of the [Zn(L ^**6** )(AcO)] complex and its liposomal formulation were compared in a syngeneic murine colon cancer model using CT-26 cells (Ribeiro et al., 2022a). The liposomal Zn(L ^**6** )(AcO) formulation demonstrated a significant reduction in tumor growth at a dose that was one-third the amount of 5-fluorouracil, with no observed systemic toxicity, thus confirming its excellent therapeutic profile. The impact of the liposomal formulation was significantly more pronounced than that of the free complex, thereby underscoring the enhanced efficacy afforded by the liposomal delivery system.

The efficacy of Cu(L ^**2** ) _**2** was evaluated in subcutaneous and metastatic murine melanoma models (Coelho et al., 2025). In vivo assays consistently demonstrated a superior therapeutic effect in animals treated with Cu(L ^**2** ) _**2** liposomes, in comparison to animals administered the free form or control groups. The results indicated the significant antimelanoma potential of the complex, particularly in nanoformulated liposomes.

The analysis of tumor mass and relative tumor volume in both studies demonstrated that the liposomal formulations were effective in inhibiting tumor growth. Furthermore, the safety assessments conducted did not demonstrate any adverse effects on the health of the organs or on hepatic function, with all parameters falling within normal ranges.

The results of the study demonstrate the superior efficacy and safety profile of the [Zn(L ^**6** )(AcO)] and Cu(L ^**2** ) _**2** liposomal formulations. These findings support the hypothesis that they have the potential to act as promising therapeutic options for the treatment of colon cancer and melanoma, respectively.

6 Conclusion

This mini-review highlights the high potential of metal complexes containing 8-hydroxyquinoline substituted with an imine at position 2 as promising anticancer agents. Through structural modifications, ligands with increased chelating rings were developed. Their complexes with a variety of metal ions, mostly from the 4^th period of the periodic table, exhibited enhanced stability and selective toxicity, rendering them promising candidates for the development of next-generation cancer therapies.

Among the metal complexes that were studied, those of Cu(II), Zn(II), V(IV)O, Ni(II), and Ru(II) derivatives demonstrated high anticancer activity for various cancer cell lines, particularly melanoma (A375), and colon cancer (HCT-116). Schiff base, hydrazone, and hydrazide-hydrazone ligands proved to be highly versatile, with metal complexes exhibiting higher levels of cytotoxicity in comparison to the free ligands and, in most cases, outperforming cisplatin and 5-FU in the cytotoxicity assays. Mechanistic studies demonstrated that most complexes act through multiple pathways, including the generation of ROS, DNA damage, the induction of apoptosis, and cell cycle arrest. Cu(II) complexes were found to be particularly effective in inducing ROS-mediated apoptosis, while Zn(II) derivatives demonstrated some selectivity towards cancer cells. Furthermore, the V(IV)O and Ru(II) complexes demonstrated cytostatic effects and anti-metastatic properties, thereby further substantiating their potential as therapeutic agents in cancer treatment.

A major limitation of metal-based therapies is their low aqueous solubility and bioavailability. In order to address this issue, nanoliposomal formulations were developed for selected Zn(II) and Cu(II) complexes. These formulations significantly enhanced the therapeutic efficacy of the complexes against melanoma and colon cancer, whilst concomitantly reducing systemic toxicity. In vivo studies confirmed that the liposomal formulations reduced tumor growth, while demonstrating suitable safety profiles.

This research provides substantial evidence to support the hypothesis that 2-imine-8HQ metal complexes are effective alternatives to conventional chemotherapy. However, further preclinical evaluation is required to ascertain the full potential of these complexes. It is recommended that future studies concentrate on the development and optimization of drug delivery systems for the cytotoxic and non-selective complexes. In addition, it is imperative to gather additional mechanistic insights to maximize therapeutic potential and selectivity.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Craig C. McLauchlan, Illinois State University, United States

Reviewed by: Ana Maria Da Costa Ferreira, University of São Paulo, Brazil

Tahmineh Kohanfekr, Payame Noor University, Iran