Next-Generation Metal Complexes in Anticancer Therapy: From Mechanism-Driven Design to Clinical Translation

1.1 Global cancer burden

Cancer is a leading cause of morbidity and mortality worldwide, responsible for an estimated 10 million deaths annually [1]. Incidence rates continue to rise due to aging populations and lifestyle factors; projections indicate a significant increase in global cancer cases over the next two decades [2]. Although early detection and targeted therapies have improved outcomes for certain tumor types, systemic chemotherapies remain indispensable in the management of many solid and hematological malignancies.

1.2 Evolution of metallodrugs

The discovery of cisplatin in the 1960s marked a watershed in medicinal chemistry, demonstrating that simple coordination complexes can exert profound biological effects [3]. Subsequent development of carboplatin and oxaliplatin sought to retain antitumor efficacy while reducing side effects. Nevertheless, platinum drugs primarily operate via DNA crosslinking and encounter limitations in selectivity and resistance.

Figure 1: Overview of non-platinum metal complexes in anticancer therapy.

Platinum therapeutics incur dose-limiting toxicities such as nephrotoxicity, peripheral neuropathy, and myelosuppression, which restrict optimal dosing [4]. Tumor resistance emerges through multiple mechanisms: enhanced DNA repair (nucleotide excision repair), increased drug efflux (ATP-binding cassette transporters), detoxification via glutathione conjugation, and inhibition of apoptotic signaling [5]. These clinical challenges underpin the ongoing search for alternative metal-based therapeutics with distinct mechanisms and improved therapeutic windows.

1.4 Rationale for next-generation metal complexes

Non-platinum metals (ruthenium, gold, copper, titanium, palladium, iridium, etc.) present rich coordination chemistry, multiple accessible oxidation states, and varied ligand architectures. These properties enable modes of action not limited to DNA crosslinking — e.g., redox modulation, enzyme inhibition, photochemical activation, and epigenetic regulation — which can address resistance and selectivity shortcomings of platinum compounds [6].

1.5 Scope and novelty of this review

This review focuses on mechanism-driven design of next-generation metal complexes and their translation from laboratory discovery to clinical testing. We place particular emphasis on structure–activity relationships (SAR), delivery strategies, and representative clinical advances to give a cohesive view bridging chemistry and medicine.

2. Classification Of Non-Platinum Metal-Based Anticancer Agents

This section groups representative non-platinum complexes by metal and highlights key ligand types, mechanisms, and current translational status. For each compound listed in Table 1.

2.1 Ruthenium complexes

Ruthenium complexes have attracted attention because of their kinetic stability, multiple oxidation states (Ru(II)/Ru(III)), and favorable ligand exchange chemistry that can be tuned for activation in biological milieus. Notable examples include NAMI-A (imidazole-containing, metastasis-inhibiting), KP1019 (indazole-based, antitumor), and NKP-1339 (a Na-derivative with improved solubility and pharmacokinetics). Mechanistically, ruthenium complexes can act via DNA binding, inhibition of metastasis pathways, and redox-mediated cytotoxicity; some are designed as prodrugs activated by reduction in the tumor microenvironment [7-9].

NAMI-A (imidazolium trans-[tetrachloro(dimethyl sulfoxide)(imidazole)ruthenate(III)])

• Primarily anti-metastatic rather than cytotoxic to primary tumors.
• Prefers binding to extracellular matrix components and inhibits tumor cell invasion [9].
• Activity is enhanced in hypoxic tumor regions due to its redox-activated Ru(III)/Ru(II) conversion.

Figure 1.2: Chemical structure of NAMI-A.  imidazolium trans-[tetrachloro (dimethyl sulfoxide) (imidazole) ruthenate (III)] complex.

• Targets mitochondria, causing rapid depolarization and apoptosis induction [10].
• Exhibits selective uptake by cancer cells due to elevated transferrin receptor expression.

Figure 1.3: Chemical structure of KP1019, an indazolium trans-[tetrachlorobis(indazole)ruthenate(III)] complex.

• A sodium salt analogue of KP1019 with improved solubility and pharmacokinetics [11].
• Induces oxidative stress and ER stress, triggering unfolded proteinactivated by reduction in the tumor microenvironment [7-9].

Figure 1.4: Chemical structure of NKP-1339, a sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] complex.

1. Electronic Effects

Electron-donating ligands (e.g., alkyl-substituted amines, methoxy-aryl) raise the Ru(III)/Ru(II) redox potential, facilitating easier reduction under hypoxic tumor conditions → ↑ activation in cancer cells[39]. Electron-withdrawing ligands (e.g., halogens, nitro-aryl) lower the redox potential, stabilizing the Ru(III) oxidation state → ↓ premature activation, ↑ stability in plasma.

2. Geometry / Coordination Environment

• Octahedral low-spin Ru(III) with bidentate N,N-ligands (as in Complex 1) offers high kinetic stability but slower ligand exchange → often reduced uptake without transport mediation[44].
• Distorted octahedral / mixed N,O coordination (Complex 2) increases ligand lability → ↑ reactivity with biomolecules, faster activation.
• Planarized chelates (Complex 3, with extended aromatic systems) enhance π–π stacking with DNA and improve passive membrane diffusion.

3. Cellular Uptake Influence

• More lipophilic ligands → ↑ passive diffusion across membranes, but risk of nonspecific binding[35].
• Hydrophilic / charged ligands rely on active transporters (e.g., transferrin receptor), increasing selectivity for cancer cells over normal tissue.
• Balanced polarity (logP ~1–3) gives optimal uptake without rapid clearance.

2.2 Gold complexes

Gold(I/III) complexes (e.g., Auranofin) show potent inhibition of thioredoxin reductase (TrxR) and related selenoenzymes, disrupting redox homeostasis and inducing apoptosis particularly in drug-resistant and hematological malignancies. Auranofin’s repurposing potential has been explored in several clinical settings, and Au(III)-porphyrin complexes add photophysical handles for combined photodynamic/chemical cytotoxicity [11-12].

Au(III)-Porphyrin

• Structurally rigid complexes that mimic platinum’s square planar geometry but are redox-active.
• Potently inhibit thioredoxin reductase (TrxR), a key enzyme in redox homeostasis, leading to ROS accumulation [12].
• Show high cytotoxicity in cisplatin-resistant tumor lines.

Figure 2: Chemical structure of a gold(III) complex with a tetradentate N-heterocyclic macrocyclic ligand coordinated to a chloride ligand.

2.3 Copper complexes

Copper-based agents (Casiopeínas, Cu-phenanthroline derivatives) leverage copper’s redox cycling ability to catalyze Fenton-like reactions in cells, raising ROS to cytotoxic levels selectively in cancer cells with already elevated oxidative stress. Additionally, copper complexes have been reported to inhibit proteasome activity and modulate signaling pathways [13-15].

Casiopeina III-ia (Cu(4,7-dimethyl-1,10-phenanthroline) (acetylacetonate))

• Capable of Fenton-like reactions, producing hydroxyl radicals that damage DNA and proteins [13].
• Chelates target nucleic acids with high affinity, causing double-strand breaks.

Figure 3: Chemical structure of a copper(II) complex containing 2,9-dimethyl-1,10-phenanthroline and an amino acid-derived ligand, coordinated with a water molecule and nitrate counterion.

Figure 3.1: Chemical structures of copper(II) complexes with various substituted phenanthroline ligands, showing different methyl, phenyl, chloro, and nitro substitutions that influence electronic properties and biological activity.

Organotitanium complexes such as titanocene derivatives exhibit unique DNA binding modes and lower nephrotoxicity relative to cisplatin. Their clinical evaluation faced formulation and stability challenges, but they remain of mechanistic interest due to different cellular processing and activation pathways [14].

Titanocene Dichloride (Cp?TiCl?)

• The first non-platinum metallodrug to enter clinical trials [14].
• Hydrolyzes under physiological conditions, releasing Ti species that bind DNA phosphate groups.
• Demonstrates immunomodulatory effects alongside direct cytotoxicity.

Figure 4: Chemical structure of titanocene dichloride, a metallocene titanium(IV) complex featuring two cyclopentadienyl ligands and two chloride ligands.

Palladium complexes, especially with extended aromatic ligands (dppz), can intercalate DNA and disrupt enzyme function. Iridium and osmium complexes are emerging for photodynamic/photocatalytic therapies owing to their strong luminescence and ability to produce singlet oxygen [17-19].

Pd(II)-Salen Complex

• Forms bidentate Schiff-base ligands with palladium, enabling DNA crosslinking similar to cisplatin but with faster ligand exchange rates [15].
• Modifications on the salen ligand allow fine-tuning of lipophilicity and cytotoxicity.

Figure 5: ORTEP diagram of a palladium(II) complex showing the coordination of bidentate N,O-donor ligands to the central Pd atom, with thermal ellipsoids depicted at the 50% probability level.

Ir(III)-Cyclometalated Complexes

• Exhibit strong phosphorescence, enabling theranostic applications [16].
• Activate under visible or near-infrared light for photodynamic therapy, generating singlet oxygen to kill cancer cells.

Figure 6: Chemical structures of a series of iridium(III) polypyridyl complexes (1–5) featuring varied ancillary ligands, illustrating structural modifications aimed at tuning their photophysical and biological properties.

Os(II)-Polypyridyl Complexes

• Display DNA intercalation and oxidative cleavage abilities [17].
• More inert ligand exchange kinetics than Ru, potentially leading to prolonged circulation times and controlled activity.

Figure 7: ORTEP representation of an osmium (II) polypyridyl complex with coordinated aromatic ligands and hexafluorophosphate counterions, showing the atomic labeling scheme and thermal ellipsoids.

Non-platinum metal complexes exert anticancer effects through multiple, often overlapping, pathways. The diversity in metal coordination chemistry allows targeting of DNA, enzymes, redox systems, and specific signaling pathways.

3.1 DNA Damage and Crosslinking

• Ruthenium (II/III) complexes (e.g., KP1019, NKP-1339) can bind to guanine N7 positions, causing mono- and bifunctional adducts that distort DNA geometry [18].
• Palladium (II) and titanium (IV) complexes also form DNA adducts, inhibiting replication and transcription.
• Some complexes intercalate between DNA base pairs, stabilizing the double helix in a distorted conformation.

3.2 Enzyme Inhibition

• Gold(I/III) complexes strongly inhibit thioredoxin reductase (TrxR), disrupting redox balance and promoting oxidative damage [19].
• Copper(II) complexes target topoisomerase I/II, hindering DNA relaxation needed for replication.
• Inhibition is often irreversible due to covalent binding with enzyme cysteine/selenocysteine residues.

3.3 Reactive Oxygen Species (ROS) Generation

• Copper and iron-mimicking Ru complexes catalyze Fenton-like reactions, generating hydroxyl radicals [20].
• ROS accumulation leads to mitochondrial membrane depolarization, cytochrome c release, and apoptosis.

3.4 Photodynamic Effects

• Iridium(III) and some osmium(II) complexes act as photosensitizers [21].
• Upon light activation, they transfer energy to oxygen molecules, generating singlet oxygen (^1O?) and triggering localized oxidative damage.

3.5 Apoptotic Pathway Activation

• Metal complexes activate intrinsic apoptosis by modulating Bcl-2 family proteins (↑ Bax, ↓ Bcl-2) [22].
• Mitochondrial outer membrane permeabilization (MOMP) leads to caspase-9 and -3 activation.
• Some complexes also engage extrinsic death receptor pathways via Fas–FasL signaling.

4. Advantages And Limitations

The design of non-platinum complexes aims to overcome platinum-based drug drawbacks such as nephrotoxicity, ototoxicity, and acquired resistance. However, limitations remain.

5. Clinical Progress and Trials

Several non-platinum complexes have entered various stages of clinical evaluation

Table 3: Clinical Trials Overview

Figure 8: Timeline of clinical progress for selected non-platinum metal-based anticancer agents

• Ligand Modification: Altering lipophilicity, charge, and steric properties to improve tumor targeting.
• Prodrug Approach: Using Ru(III) prodrugs activated in hypoxic tumors.
• Nanocarrier-Based Delivery: Encapsulation in liposomes, polymeric nanoparticles to improve biodistribution.
• Tumor Microenvironment Targeting: Designing complexes responsive to pH, glutathione levels.
• Combination Therapies: Pairing with kinase inhibitors, immunotherapy to enhance effects.

Figure 9: Schematic representation of strategies to improve the selectivity of metal-based anticancer drugs.