Evolution of Metal-Based Anticancer Therapeutics: Chemical Foundations, Platinum Drugs, and Emerging Schiff Base Ruthenium(II) and Iridium(III) Complexes

Abstract

Metal-based chemotherapy has remained a cornerstone of cancer treatment since the clinical introduction of cisplatin; however, systemic toxicity, dose-limiting nephrotoxicity, and acquired resistance continue to limit its therapeutic efficacy. These challenges have stimulated the development of non-platinum-metal-based agents, particularly ruthenium­(II/III) and iridium­(III) complexes, which offer tunable coordination environments, redox adaptability, and diverse mechanisms of action. Among the ligand systems investigated, Schiff bases have emerged as versatile scaffolds capable of modulating complex stability, lipophilicity, and target selectivity. This Review critically examines recent advances (2023–2025) in Schiff base ruthenium and iridium complexes, with emphasis on their structure–activity relationships and anticancer mechanisms. Recent Schiff base Ru­(II/III) complexes have demonstrated promising DNA-binding, redox-modulating, and apoptosis-inducing properties, whereas several Ir­(III) complexes exhibit potent cytotoxicity, phosphorescence imaging capability, and phototherapeutic potential, supporting their development as theranostic agents. Mechanistic studies reveal multimodal activity involving DNA interactions, human serum albumin (HSA) binding, reactive oxygen species (ROS) modulation, mitochondrial dysfunction, and apoptosis induction. Emerging strategies, including NIR-activated phototherapy, nanocarrier-assisted delivery, and computational approaches such as molecular docking and density functional theory (DFT) calculations, are further highlighted as promising directions for the rational design of next-generation metal-based anticancer therapeutics.

1. Introduction

Coordination chemistry provides a highly versatile framework for designing metal complexes with remarkable structural diversity and functional tunability. , The selective interaction of transition metals with biomolecules, nucleic acids, serum proteins, and enzymes has positioned coordination compounds at the forefront of therapeutic and diagnostic research. ,

The clinical success of cisplatin in treating testicular, ovarian, and non-small-cell lung cancers established platinum-based chemotherapy as a legitimate treatment paradigm. Despite this, dose-limiting nephrotoxicity, peripheral neurotoxicity, and intrinsic or acquired resistance substantially restrict its broader application. , These limitations have stimulated the development of non-platinum transition-metal complexes, particularly ruthenium and iridium compounds, as alternative anticancer agents.

Among the emerging metal-based therapeutics, ruthenium and iridium complexes have attracted considerable attention, owing to their diverse oxidation states, favorable coordination chemistry, tunable ligand environments, and unique mechanisms of action. Unlike platinum drugs, these complexes can be rationally designed to modulate cellular uptake, biomolecular recognition, redox behavior, and intracellular targeting. In addition, both Ru­(II) and Ru­(III) complexes have demonstrated significant therapeutic potential, with Ru­(III) species often functioning as prodrugs activated under the reducing conditions of the tumor microenvironment.

Schiff base ligands represent one of the most extensively investigated ligand classes in medicinal inorganic chemistry because of their straightforward synthesis, structural versatility, strong metal-coordinating ability, and ease of functional modification. Coordination of Schiff bases with ruthenium and iridium centers frequently enhances complex stability, lipophilicity, DNA-binding affinity, and biological activity. Consequently, Schiff base Ru and Ir complexes have emerged as a promising class of metal-based anticancer agents, exhibiting notable cytotoxic, apoptotic, and biomolecular interaction properties.

Several recent reviews have highlighted the therapeutic potential of metal-based anticancer agents, ruthenium complexes, iridium complexes, and Schiff base coordination compounds individually. However, most of these reviews have focused on broad classes of metal-based drugs or were published before the recent expansion of studies reported between 2023 and 2025. A dedicated assessment integrating recent advances in Schiff base ruthenium and iridium complexes, structure–activity relationships, biomolecular interactions, mechanistic insights, and emerging therapeutic strategies remains limited. Therefore, the present review provides an updated and comprehensive overview of recent developments in this rapidly evolving field, highlighting chemical design principles, biological performance, and future opportunities for anticancer drug development.

2. Discussion

Despite substantial advances in the design of ruthenium­(II) and iridium­(III) complexes, their clinical translation remains limited. A major challenge lies in the inconsistency between promising in vitro cytotoxicity and insufficient in vivo efficacy, often arising from poor pharmacokinetic stability, rapid systemic clearance, and off-target interactions. Furthermore, variability in experimental models and the lack of standardized biological evaluation make cross-comparison of reported complexes difficult. Although Schiff base ligands offer structural versatility, issues related to long-term toxicity, metabolic fate, and large-scale reproducibility have not been sufficiently addressed. These limitations highlight the need for more rigorous in vivo validation, standardized evaluation protocols, and clinically relevant study designs to enable the successful translation of these complexes into therapeutic applications.

2.1. Limitations of Platinum-Based Chemotherapy and the Rationale for Ru/Ir Alternatives

Cisplatin and its second-generation analogue carboplatin, while clinically effective against multiple solid tumors, share fundamental pharmacological liabilities: poor tumor selectivity, nephrotoxicity requiring intensive hydration protocols, cumulative peripheral neuropathy, and resistance arising through nucleotide excision repair (NER) upregulation, reduced CTR1-mediated drug uptake, and Bcl-2-driven antiapoptotic signaling. These shortcomings have motivated the investigation of ruthenium and iridium complexes, which offer orthogonal mechanisms of action, redox-responsive activation, and ligand tunability unavailable to square-planar platinum compounds.

2.1.1. Need for Better, Smarter Metal-Based Drugs

Beyond platinum, researchers have turned to second-row and third-row transition metals, particularly ruthenium, iridium, gold, and copper, which offer distinct oxidation state flexibility, kinetic properties, and ligand tunability that enable entirely new mechanisms of therapeutic action (Figure ). This shift from platinum-centric to broad transition-metal drug design marks a paradigm change that forms the central subject of this review. −

1.

Development timeline of Ru and Ir complexes.

2.2. Emergence of Ruthenium and Iridium Complexes as Anticancer Agents

Ruthenium and iridium complexes have emerged as leading alternatives to platinum drugs due to their favorable chemical and biological properties. These complexes exhibit key features such as redox flexibility, kinetic stability, and ligand tunability. Such attributes have positioned Ru and Ir complexes as promising alternatives to platinum drugs, offering therapeutic benefits that extend beyond the limitations of conventional chemotherapy.

2.3. Ru and Ir Complexes: Advantages over Platinum-Based Chemotherapy

In recent years, complexes of Ru and Ir have surfaced as encouraging substitutes for conventional platinum-based medications like cisplatin. , A key characteristic of ruthenium is its capacity to appear in various oxidation states (II, III, and IV), enabling the creation of redox-active complexes that respond to the tumor microenvironment. Significantly, Ru­(III) prodrugs can be specifically triggered under the hypoxic and acidic environments common in many tumors, facilitating targeted drug delivery and lowering systemic toxicity.

Moreover, both Ru and Ir complexes show reduced ligand exchange rates relative to those of platinum, leading to enhanced stability in blood plasma and extended circulation durations. This kinetic stability boosts selective absorption in tumors and reduces off-target interactions. Additionally, the ability to adjust ligands in these complexes enables medicinal chemists to create highly tailored scaffolds with distinct functional characteristics. The inclusion of polydentate ligands, bioactive components, or photoresponsivity elements creates many therapeutic possibilities, such as photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Together, these characteristics make Ru and Ir complexes structurally flexible, biologically reactive, and pharmacologically diverse.

The drug Ru and Ir complexes have been developed as anticancer agents in large part due to the inability of cisplatin therapy to overcome the shortcomings of this drug. In contrast to cisplatin, which acts mainly on nuclear DNA and tends to be inefficient against drug-resistant tumors because of pathways causing repair of DNA or a difference in drug intake, Ru and Ir complexes show a multifunctional mechanism of action. These complexes exhibit multifunctional mechanisms, interacting with DNA, proteins, enzymes, and mitochondria, thereby enhancing cytotoxicity and reducing resistance. As an example, compounds KP1019 and NAMI-A are Ru­(III) complexes that have been proven to cause apoptosis by disturbing mitochondrial functionality, producing ROS, and affecting the ridge of important signaling cascades such as the p53 and MAPK pathways. These complexes are effective not only in rapidly proliferating cells but also in nonreplicative tumor environments (Table ).

1. Clinical Development History and Challenges of Platinum-, Ruthenium-, and Iridium-based Anticancer Complexes.

Drug Name	Metal	Company/Developer	Trial Phase	Status	Main Reason for Failure/Discontinuation	Notable Remarks
NAMI-A	Ru	Italian research groups/Antibe Therapeutics	Phase I/II	Discontinued	Insufficient efficacy as monotherapy; not cytotoxic to primary tumors	First Ru-based antimetastatic drug; active against metastasis, not primary cancer
KP1019	Ru	University of Vienna/PharmaMar	Phase I	Trials ended	Water insolubility limited further clinical progress; moderate efficacy	Led to development of more soluble NKP1339 (see below)
NKP1339	Ru	Vienna researchers	Phase I	Ongoing/interrupted	Still under evaluation; further development dependent on results	Sodium salt of KP1019; improved solubility
Satraplatin	Pt	GPC Biotech/Novartis	Phase III	Discontinued	Failed to meet clinical end points; insufficient efficacy	Oral platinum; renal and GI toxicities
Picoplatin	Pt	Poniard/BIND Therapeutics	Phase III	Discontinued	Lack of efficacy over existing treatments; toxicity issues	Developed for platinum-resistant tumors
RAPTA family	Ru	Academic (Sadler group and others)	Preclinical/early clinical	Ongoing/exploratory	Yet to reach late-phase clinical trials	Promising antimetastatic action; focus on protein targets
Ir(III) complexes	Ir	Academic + industry	Preclinical/early clinical	Ongoing/exploratory	Yet to prove sufficient safety/efficacy in advanced trials	Mechanistically diverse, but clinical progress less advanced than Ru
BOLD-100	Ru	Bold Therapeutics	Phase I/II	Ongoing	-	Most advanced Ru candidate as of recent years

Additionally, other targets besides the DNA, such as the topoisomerase enzymes, cyclin-dependent kinase 2 (CDK2), and numerous types of protein kinases, are also inhibited by these complexes, giving the prospects of selective cancer subtype targeting and synergistic combinations with other chemotherapeutics. Nevertheless, many Ru and Ir compounds have been unable to overcome great obstacles in their clinical translation despite their promising properties. The pioneer antimetastatic treatments, such as NAMI-A, although innovative on a noncytotoxic mechanism of antimetastatic activity, ended up disappointing in Phase II clinical testing because they conferred insufficient monotherapeutic efficacy. In the same light, it can be said that other complexes of Ru like picoplatin and satraplatin have been set back due to their toxicity profile or their inability to prove themselves superior to current therapies in the latter-stage trials. These historical barriers document how tricky it is to translate the flexible chemistry of Ru and Ir into therapies that are effective and safe enough to use in the clinic. , Nonetheless, these challenges are expected to be addressed by continuous research and development into rational drug design, based on the comprehensive structure–activity relationship (SAR) chemistry, better formulation platforms, and patient selection, as properly supported by the tumor metabolic and molecular profiling. Utilization of this personalized medicine platform by taking advantage of the distinct pharmacological action of Ru and Ir complexes as an individualized approach to cancer treatment offers potential solutions to tailoring effective treatments based on tumor biology to circumvent the deficiency that has been witnessed with cisplatin and has elevated hope of effective and targeted cancer treatment. However, despite these advantages, challenges related to pharmacokinetics, off-target effects, and limited clinical validation continue to hinder their translation to approved therapies.

In addition to Ru­(II) complexes, Ru­(III) compounds have attracted considerable attention as anticancer agents owing to their prodrug characteristics and preferential activation under reducing conditions of the tumor microenvironment. Notable examples include NAMI-A, KP1019, and NKP1339, which have demonstrated promising preclinical and clinical potentials. Recent Schiff-base Ru­(III) complexes have also exhibited significant cytotoxic activity, further highlighting the therapeutic relevance of this oxidation state.

2.4. Coordination Architectures of Ruthenium and Iridium Complexes with Therapeutic Potential

2.4.1. Polypyridyl-Type Complexes

Ligands such as bipyridine (bpy), phenanthroline (phen), and terpyridine (tpy) create stable and rigid chelates with Ru­(II) and Ir­(III), resulting in complexes with outstanding photophysical and biological characteristics. These complexes are usually very planar and can be inserted between DNA base pairs, hindering replication and transcription. Additionally, numerous polypyridyl complexes show intense luminescence and photoactivity, rendering them appropriate for theranostic uses that integrate imaging and treatment.

Apart from targeting DNA, Ir­(III) polypyridyl complexes can influence mitochondria by disturbing the membrane potential, increasing ROS levels, and triggering mitochondrial-dependent apoptosis. These complex actions enable them to bypass traditional resistance strategies and deliver strong cytotoxic effects in both normoxic and hypoxic tumor environments. Their capacity to function in hypoxic conditions is particularly important since numerous conventional drugs lose effectiveness in these environments. Numerous Ru and Ir polypyridyl complexes have demonstrated IC₅₀ values in the low micromolar range.

2.4.2. Representative Ru/Ir Complexes in Clinical and Preclinical Stages

Advancements in Ru and Ir complex studies have led to actual clinical investigations. Four ruthenium complexes, NAMI-A, KP1019, NKP1339, and TLD1433, are undergoing clinical trials, showing tumor reduction, antimetastatic properties, and better tolerability in comparison to cisplatin (Figure , Table ). For example, TLD1433 is presently in clinical trials for bladder cancer as a PDT agent, utilizing light activation to produce cytotoxic singlet oxygen exclusively in the tumor tissue. These instances highlight the potential for these metal complexes to be translated from the laboratory to clinical applications.

2.

Representative structures of clinically investigated ruthenium complexes, highlighting their coordination environments and therapeutic relevance.

2. Representative Ruthenium and Iridium Complexes in Clinical and Preclinical Development.

Complex Name	Metal Center	Ligand Type	Cancer Target	Mode of Action	Clinical Status
NAMI-A	Ru(III)	Imidazole, DMSO	Lung, Metastatic	Antimetastatic, Non-DNA binding	Phase I/II
KP1019	Ru(III)	Indazole	Colon, Ovarian	DNA interaction, apoptosis	Phase I
NKP1339	Ru(III)	Sodium salt of KP1019	Gastrointestinal	ROS generation, mitochondrial disruption	Phase I/II
RAPTA-C	Ru(II)	PTA, arene	Breast, Prostate	Antimetastatic, protein interaction	Preclinical
[Cp*IrCl(N∧N)]	Ir(III)	Polypyridyl	Lung, Liver	DNA damage, ROS induction	Preclinical

Additionally, these metal complexes do not depend on one specific target or mechanism, which reduces their vulnerability to the development of resistance. Research indicates that they can hinder angiogenesis, reduce metastasis, disrupt tumor glycolysis, and affect various signaling pathways. In certain situations, such as NKP1339, using combination therapy with medications such as sorafenib has produced enhanced anticancer effects. These characteristics correspond with the increasing focus on precision medicine, where therapies are customized not only to the tumor type but also to its molecular and metabolic traits.

These transition metals in the second and third rows provide unique chemical, biological, and pharmacological benefits that overcome various drawbacks associated with platinum treatment. A key characteristic of ruthenium is its capacity to appear in various oxidation states (II, III, and IV), enabling the creation of redox-active complexes that respond to the tumor microenvironment. Significantly, Ru­(III) prodrugs can be specifically triggered under the hypoxic and acidic environments common in many tumors, facilitating targeted drug delivery and lowering systemic toxicity (Table ).

These structural categories serve as the basis for additional advancements and clinical assessments (Table ). Recent studies have expanded on these architectures to enhance biological efficacy, as outlined in the next section concerning research developments and SAR findings.

3. Comparison of Ru/Ir vs Pt Complexes in Anticancer Therapy.

Feature	Platinum Complexes	Ru/Ir Complexes
Primary Target	Nuclear DNA	DNA, mitochondria, proteins, enzymes
Activation Mechanism	Passive diffusion	Redox activation, light activation
Resistance Profile	High (e.g., enhanced DNA repair)	Effective in cisplatin-resistant lines
Toxicity	High (nephrotoxicity, neurotoxicity)	Generally lower toxicity
Selectivity	Low	Enhanced via transferrin-mediated uptake
Clinical Advancement	FDA approved	Several in trials (NAMI-A, KP1019)

2.5. Research Advances and SAR Insights in Ru/Ir Complexes

2.5.1. Ir­(III) Complexes: Luminescence and Biostability

Ir­(III) complexes are increasingly recognized for their dual potential as anticancer agents and luminescent probes. Their structural backbone often involves cyclometalated (C^∧N) and polypyridyl (N^∧N) ligands, which confer exceptional kinetic stability, photophysical properties, and biocompatibility. , This chemical robustness allows Ir­(III) complexes to maintain their integrity under physiological conditions, making them ideal candidates for long-circulating or organelle-targeted therapies. Furthermore, many Ir­(III) complexes exhibit strong phosphorescence, which has been harnessed for bioimaging, cell tracking, and theranostics, enabling real-time monitoring of drug localization and efficacy.

In therapeutic applications, Ir­(III) complexes typically induce apoptosis through ROS generation, mitochondrial membrane potential disruption, or cell-cycle arrest. Some have also demonstrated selective accumulation in lysosomes or nuclei, allowing for organelle-specific action. Importantly, structural flexibility enables modification for light-triggered activation, which has led to the development of photoactivated iridium complexes for targeted PDT. Several recent studies report Ir­(III) complexes with submicromolar IC₅₀ values against various cancer cell lines, including those resistant to platinum drugs, positioning them as valuable tools in both therapeutic and diagnostic oncology.

2.5.2. Schiff Bases as Bioactive Ligands

Schiff base ligands are widely used because of their structural tunability and strong metal chelation ability. When integrated into Ru or Ir complexes, Schiff bases promote the creation of stable, lipophilic, and biologically active chelates, improving cellular absorption and therapeutic efficacy. Their capacity to create bidentate or polydentate structures leads to stiff geometries that improve selectivity for biological macromolecules.

The bioactivity of Schiff base complexes is significantly enhanced when modified with pharmacophores, redox-active groups, or side ligands that can intercalate or interact enzymatically. , These systems have demonstrated the ability to bind DNA through groove binding or intercalation, inhibit topoisomerase, or interfere with protein function via metal–ligand exchange reactions. The adaptability of Schiff bases also renders them ideal for targeted delivery, responsive drug release, or dual roles in imaging and therapy, establishing them as a crucial platform in the continued advancement of Ru- and Ir-based metallodrugs (Figure , Table ).

3.

Schematic representation of Ru­(II)/Ir­(III) complexes showing their coordination architectures, biological targets, and clinical development pathway.

4. Recent Schiff Base Ru/Ir Complexes and Their Anticancer Activities.

Reference	Metal	Structural Feature	Activity
Ramadan et al.	Ru(III)	Schiff base	IC50 = 4.97 μg/mL
Liu et al.	Ir(III)	Fluorescent Schiff base	Enhanced cytotoxicity
Behera et al.	Ir(III)	Difluoro-substituted ligand	Potent activity
Kostova et al.	Ir(III)	Organometallic Ir(III)	High cytotoxicity
Bermejo-Casadesús et al.	Ir(III)	Cyclometalated Ir(III)	PDT activity

2.5.3. Coordination Environment vs Cytotoxicity/Selectivity

Recent SAR studies on Ru­(II) and Ir­(III) complexes have uncovered various structural elements that significantly affect the anticancer efficacy. Initially, ligand modification, especially the addition of electron-rich, hydrophobic, or sterically bulky groups, can significantly enhance cellular permeability, DNA interaction, and subcellular distribution. Second, cationic complexes typically exhibit greater cytotoxicity than neutral ones, probably owing to improved interaction with negatively charged cellular membranes and DNA. Utilizing large ligands additionally aids in avoiding deactivation by glutathione or serum proteins, extending biological activity. Despite these advances, inconsistencies in biological evaluation and a lack of standardized in vivo studies limit direct comparison and clinical progression.

2.6. Biological Activity and Mechanistic Insights

Biological evaluation of Ru­(II) and Ir­(III) complexes in recent studies primarily focuses on cytotoxicity profiling, DNA/protein interactions, and mechanistic validation through cellular assay. , Recent studies demonstrate that Ru­(II) and Ir­(III) complexes interact with DNA primarily through intercalation and groove binding, as evidenced by spectroscopic and viscosity-based analyses. , For instance, several Schiff base complexes reported in 2023–2025 exhibit strong binding affinity, correlating with enhanced cytotoxicity and apoptosis induction in cancer cells (Figure ).

4.

Mechanistic pathways of ruthenium and iridium complexes through DNA binding, HSA interaction, and ROS generation.

Biological evaluation of recent Schiff base Ru­(II) and Ir­(III) complexes reveals a consistent pattern of multimodal action. DNA interaction studies using UV–vis spectroscopy, fluorescence displacement, and viscosity measurements confirm intercalation and groove-binding as the dominant binding modes, with binding constants (K _b) typically in the range of 10⁴–10⁶ M^–1. HSA binding studies using fluorescence quenching yield association constants of 10³–10⁵ M^–1, with thermodynamic parameters indicating predominantly hydrophobic and hydrogen-bonding interactions that support favorable pharmacokinetic profiles. Cytotoxic activity across A549, HeLa, MDA-MB-231, and cisplatin-resistant cell lines is frequently reported in the low micromolar to submicromolar range, with Selectivity Index (SI) values exceeding 2 for several Schiff base systems, pointing to meaningful therapeutic windows. ,

Interaction with serum proteins, particularly human serum albumin (HSA), plays a key role in modulating the pharmacokinetics of Ru­(II) and Ir­(III) complexes. Recent studies report moderate to strong binding affinities, which contribute to improved stability and bioavailability, although excessive binding may reduce therapeutic efficacy. ,

Cytotoxicity evaluation of Ru­(II) and Ir­(III) complexes across multiple cancer cell lines consistently demonstrates activity in the low micromolar to submicromolar range. Several recent Schiff base complexes show enhanced selectivity toward cancer cells compared to normal cells, with improved efficacy in cisplatin-resistant models.

2.7. Recent Developments in Schiff Base Ru­(II)/Ir­(III) Complexes: Synthesis, Biological Activity, and Mechanistic Insights

In recent years, significant attention has been directed toward the development of ruthenium- and iridium-based complexes as alternatives to platinum-based chemotherapy. , Unlike cisplatin, which suffers from systemic toxicity and resistance, these transition-metal complexes provide versatile redox chemistry, tunable ligand environments, and the ability to engage biomolecular targets with enhanced selectivity. Current research (2023–2025) has provided strong evidence that careful ligand design, particularly Schiff base and anthraquinone frameworks, can dictate cytotoxicity, stability, and therapeutic specificity.

Ruthenium complexes remain at the forefront of this field. Ramadan et al. (2025) reported a series of mononuclear Ru­(III) Schiff-base complexes, structurally confirmed by spectroscopy and DFT, which demonstrated potent cytotoxic activity against colorectal, breast, and liver cancer cell lines. The complexes showed IC₅₀ values as low as 4.97 μg/mL, rivaling vinblastine, and docking studies revealed strong interactions with DNA, suggesting dual roles in redox modulation and direct nucleic acid engagement. Similarly, Karabıyık et al. (2024) synthesized Ru­(II) arene Schiff-base complexes that exhibited selective cytotoxicity toward lung carcinoma (A549) cells, where variations in the arene moiety directly influenced DNA intercalation efficiency and apoptosis induction. Complementing these findings, Es-Sounni et al. (2024) described Ru­(II) tetradentate salen Schiff-base systems that combined anticancer potency with pronounced antioxidant activity in DPPH and FRAP assays, highlighting the emerging theme of multifunctionality where metallodrugs not only kill cancer cells but also modulate oxidative balance. Further expanding the Ru­(II) Schiff-base landscape, Alkış et al. (2021) demonstrated that cobalt and ruthenium complexes bearing pyrimidine-based Schiff base ligands exhibit notable anticancer activity alongside electrochemotherapy-enhancing properties, with the Ru complex showing superior cytotoxic potency compared to its cobalt analogue. This comparison underscores the importance of metal center identity in governing biological outcome even when the ligand scaffold is held constant, a finding with direct implications for rational lead selection in Schiff-base metallodrug design. Collectively, these studies underscore that Schiff-base functionalization, arene identity, and ancillary ligand substitution remain key design principles in tailoring ruthenium complexes for selective therapeutic outcomes.

Parallel progress has been achieved with iridium complexes, where photophysical properties complement cytotoxic action. Liu et al. (2025) designed triphenylamine-decorated half-sandwich Ir­(III) Schiff-base complexes that exhibited strong phosphorescence and notable selectivity, showing ∼2.5-fold higher cytotoxicity than cisplatin in A549 and cisplatin-resistant A549/DDP lung cancer cells, while sparing normal lung epithelial cells. Importantly, their luminescent behavior indicated potential for bioimaging applications alongside therapy, a hallmark of theranostic design. Expanding the scope, Kostova et al. (2025) reported thiazole-based Ir­(III) half-sandwich complexes with excellent stability and high cytotoxic activity against glioblastoma (LN-229) and triple-negative breast cancer (MDA-MB-231) cells, where ct-DNA binding studies confirmed strong intercalation and groove-binding interactions. These results were further contextualized by Štarha (2025), who reviewed recent advances in Ir-Cp* half-sandwich complexes, highlighting their ability to integrate PDT mechanisms, selective ROS generation, and mitochondrial targeting features that distinguish them from ruthenium analogues. Extending this further, Behera et al. (2025) reported bis-heteroleptic Ir­(III) complexes bearing difluoro-substituted phenylpyridine ligands that demonstrated significant anticancer efficacy across multiple cell lines. The fluorine substitution enhanced the electron-withdrawing character of the cyclometalated ligand, increasing the metal’s oxidizing power and ROS generation capacity, while simultaneously improving cellular uptake. This study reinforces the emerging consensus that halogen substitution on the cyclometalating ligand is a reliable handle for tuning both photophysical and cytotoxic properties in Ir­(III) anticancer systems.

Mechanistic studies across both metal systems converge on a common theme: robust DNA/HSA binding, coupled with finely tuned redox activity, underpins selective anticancer efficacy. Fluorescence quenching and viscosity measurements confirm groove and partial intercalation modes of DNA interaction, while thermodynamic analyses of serum albumin binding suggest that hydrophobic and hydrogen-bonding forces govern systemic distribution. Furthermore, both ruthenium and iridium complexes show dual oxidative behavior: intracellular ROS induction leading to apoptosis, alongside measurable radical-scavenging capacity in antioxidant assays. This balance between pro-oxidant and antioxidant effects is increasingly recognized as central to minimizing off-target toxicity while maintaining therapeutic potency.

Collectively, recent advances reported between 2023 and 2025 demonstrate that Schiff base ruthenium and iridium complexes continue to evolve beyond conventional cytotoxic agents toward multifunctional platforms capable of biomolecular targeting, redox modulation, imaging, and phototherapeutic applications. These developments further reinforce their potential as next-generation metal-based anticancer therapeutics. ,

To facilitate comparison of recent structure–activity relationship (SAR) trends, the key Schiff base Ru­(II) and Ir­(III) complexes reported between 2023 and 2025 are summarized in Table , highlighting representative ligand modifications, cytotoxicity profiles, and proposed mechanisms of action.

3. Future Directions

Despite significant advances, several challenges and opportunities remain in the development of Schiff-base Ru­(II) and Ir­(III) anticancer complexes. First, the rational design of tumor-selective complexes through targeted ligand modification, incorporating bioactive vectors such as peptide sequences or folate groups that exploit overexpressed receptors in cancer cells, remains underexplored. Second, the integration of Ru­(II) and Ir­(III) Schiff base frameworks into nanocarrier platforms, including liposomes, polymeric nanoparticles, and metal–organic frameworks (MOFs), offers a promising strategy to overcome pharmacokinetic limitations and enhance tumor accumulation via passive and active targeting. Third, photoactivatable complexes designed for PACT and PDT applications represent a rapidly growing area, with future work needed to extend photoactivation wavelengths into the near-infrared (NIR) range for deeper tissue penetration. Fourth, the application of computational tools, including DFT, molecular docking, and machine-learning-guided SAR, should be systematically integrated into the drug discovery pipeline to accelerate the identification of lead compounds with optimized biological profiles. Finally, rigorous in vivo pharmacokinetic and toxicity studies, combined with robust mechanistic investigations in clinically relevant tumor models, are essential prerequisites for translating promising preclinical candidates to clinical evaluation. Collectively, advancing these directions will be critical for realizing the full therapeutic potential of Schiff-base Ru­(II) and Ir­(III) complexes as next-generation anticancer agents.

Ruthenium­(II) and iridium­(III) complexes coordinated with Schiff bases mark a substantial improvement over traditional platinum-based chemotherapy, overcoming major issues such as systemic toxicity and drug resistance. Their structural flexibility, adjustable redox properties, and kinetic resilience facilitate multitargeted anticancer actions that go beyond DNA cross-linking to encompass mitochondrial disruption, modulation of reactive oxygen species, enzyme inhibition, and activation of apoptotic pathways. Unlike conventional platinum compounds, these complexes show enhanced selectivity and possible effectiveness against resistant and hypoxic tumor models.

4. Conclusion

Recent advancements in translation, featuring clinically progressed ruthenium compounds and photoactivatable systems, highlight the increasing therapeutic significance of transition-metal platforms. Nonetheless, issues concerning formulation, pharmacokinetics, large-scale production, and late-stage clinical validation persist as major obstacles to broad clinical acceptance. Surmounting these challenges will necessitate logical structure–activity enhancement, better biomarker-informed patient classification, and the incorporation of nanotechnology and combination treatments.

Despite substantial progress, key challenges, including pharmacokinetic limitations, large-scale synthesis, and insufficient clinical validation, remain. Addressing these issues through rational design, nanotechnology, and precision medicine approaches is essential for successful translation. Overall, Schiff-base Ru and Ir complexes represent a promising platform for next-generation anticancer therapeutics.

Glossary

Abbreviation

CC₅₀

50% Cytotoxic Concentration

AO/EB

Acridine Orange/Ethidium Bromide

ATR

Ataxia Telangiectasia and Rad3-related protein kinase

ATM

Ataxia Telangiectasia Mutated kinase

Bcl-2

B-cell Lymphoma 2

ct - DNA

Calf Thymus Deoxyribonucleic Acid

Chk1

Checkpoint Kinase 1

Chk2

Checkpoint Kinase 2

CTR1

Copper Transporter 1

CDK2

Cyclin-dependent kinase 2

FDA

Food and Drug Administration

IC₅₀

Half-Maximal Inhibitory Concentration

HSA

Human Serum Albumin

Ir

Iridium

MAPK

Mitogen-Activated Protein Kinase

MRP2

Multidrug Resistance-associated Protein 2

NDA

New Drug Application

NER

Nucleotide Excision Repair

PACT

Photoactivated Chemotherapy

ROS

Reactive oxygen species

Ru

Ruthenium

SAR

Structure Activity Relationship

p53

Tumor Protein p53

WHO

World Health Organization

The authors declare no competing financial interest.