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DOI: 10.1055/s-0043-1773514
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Small Molecules in Medicinal Chemistry

Ruthenium-Based Small-Molecule Complexes: A Promising Approach for Drug Discovery

Priyank Purohit  ∗
a   Himalayan School of Pharmaceutical Science, SRHU, Jolly Grant Swami Ram Nagar, beside Jolly Grant Airport, Dehradun, Uttarakhand 248016, India
,
Akanksha Bhatt
b   School of Pharmacy, Graphic Era Hill University, Dehradun, 248001, India
,
Ravi Kumar Mittal
c   Galgotias College of Pharmacy, Greater Noida, Uttar Pradesh, India
› Author Affiliations
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Abstract

The paradigm of cancer treatment has been shifting from traditional approaches to metal-based therapies; however, achieving effective and targeted treatments remains a significant challenge. The journey of metal-based drugs began with the serendipitous discovery of cisplatin, which paved the way for the development of various platinum derivatives. Additionally, other metals, such as ruthenium (Ru), nickel (Ni), zinc (Zn), and copper (Cu), have been explored for their therapeutic potential. Among these, ruthenium-based complexes stand out due to their unique redox properties, high selectivity, and remarkable chelation capabilities, making them promising candidates for cancer therapy. This Account aims to provide a comprehensive overview of the journey of ruthenium-based metal complexes, their current status, and their pharmacological and chemical classification. These pharmacophores enable the selective delivery of cytotoxic payloads to cancer cells while sparing healthy cells. Notably, the ruthenium complex IT-139 (formerly NKP-1339) has demonstrated significant promise in clinical studies for various cancer types, exhibiting a lower toxicity than platinum-based therapies. The Account also highlights other ruthenium-based complexes and their advances. It aims to provide readers with a detailed understanding of the role of ruthenium in metal-based drug development, its mechanisms of action, and its potential applications in personalized cancer treatments. This exploration underscores the potential of ruthenium complexes, both with and without active molecules, to emerge as safe and effective therapeutic candidates in clinical oncology.

1 Introduction

2 Importance of Ruthenium Metal and its Complexes

3 Synthesis of Ruthenium Complexes

4 Classification of Ruthenium Complex Antitumor Drugs Based on their Mode of Action

5 Classification of Ruthenium Complex Antitumor Drugs Based on their Structure and the Oxidation State of Ruthenium

6 Current Status of Drug Clinical Trials

7 Status and Applications of Metals Other than Ruthenium

8 Conclusion


#

Key words

ruthenium complexes - metal-based pharmacophores - cancer therapy - NKP-1339 - redox activity - medicinal chemistry

Biographical Sketches

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Dr. Priyank Purohit is currently serving as an Associate Professor at Swami Rama Himalayan University (SRHU), Jolly grant. He has published 31 international research papers, including in high-impact journals such as ACS and RSC, and holds two granted patents. Dr. Purohit is also supervising five PhD students in his research group. He completed both his M.S. and PhD from the prestigious National Institute of Pharmaceutical Education and Research (NIPER), Mohali, where he was honoured with the Best Thesis Award from the Department of Science and Technology (DST) for his outstanding research. His current research interests focus on metal and metal interactions with polymers, polymer modifications, and polymer medicinal chemistry. Dr. Purohit’s work aims to explore innovative approaches in these areas to advance the development of new materials and therapeutic strategies.

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Mrs. Akanksha Bhatt is currently pursuing her PhD under the supervision of Dr. Priyank Purohit. She is also serving as an Assistant Professor at Graphic Era University. Mrs. Bhatt has published six SCI-indexed papers from her PhD thesis, contributing significantly to the field. Her research primarily focuses on polymer modification, specifically the development and application of polymers as active pharmaceutical ingredients (APIs) and excipients. She completed her M. Pharm from Shri Guru Ram Rai University (SGRRA), where she developed a strong foundation in pharmaceutical sciences. Mrs. Bhatt’s ongoing research aims to innovate in polymer applications to enhance drug delivery and formulation technologies.

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Dr. Ravi Kumar Mittal is presently serving as an Associate Professor at Galgotias College of Pharmacy, Greater Noida, Uttar Pradesh, India. He has made significant contributions to the field of pharmaceutical sciences, with over 25 research and review articles published in esteemed international journals. Dr. Mittal completed his PhD at the National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, a premier institution recognized for excellence in pharmaceutical education and research. His research interests encompass the synthesis and characterization of quinoline-based compounds, with a particular focus on their potential applications in anticancer and antiviral therapeutics. Additionally, his work explores the role of nutraceuticals in promoting health and preventing disease, reflecting a multidisciplinary approach to addressing critical healthcare challenges. Driven by a commitment to innovation, Dr. Mittal aims to develop novel strategies for the design and discovery of therapeutic agents

1

Introduction

The foundations of contemporary drug discovery rely on small molecules because these tend to engage with specific biological targets and frequently act as highly effective drugs. Small-molecule medications are artificial compounds intended to imitate, intensify, or decrease the actions of organic compounds or bodily products. They are superior to macromolecules (Figure [1]) because of their comparatively simple structures, which can be altered to achieve various therapeutic objectives. Patients can easily follow simple, frequently oral, dosing procedures because small-molecule drugs often behave predictably inside the body, are stable, and rarely require specific storage conditions. Because they are quickly absorbed by the body then travel from the gut to the site of action through the bloodstream and penetrate the membranes of cells to reach intracellular targets, they are effective in treating a broad range of disorders. They are exceptionally versatile because they can be used as injectables, suppositories, inhalers, or tablets.[1] [2] [3]

Small compounds can be engineered to engage preferentially with particular biological targets by modifying their chemical structure. Small molecules can be made to achieve specific purposes by changing their atomic makeup, so that they only cause the intended action. The ability to investigate an entire chemical space in this manner provides small-molecule techniques with a significant edge over other modalities, due to their versatility. Researchers must use synthetic mastery and rigorous design over several years to create a small-molecule medication that minimizes undesired side effects while functioning precisely as it should.[4] [5]

The application of artificial intelligence (AI) in drug discovery has revolutionized pharmaceutical research. The ability of AI to analyze massive amounts of information, predict chemical interactions, and speed up compound screening gives it a competitive edge. These tools can swiftly simulate drug-target interactions, predict toxic effects and efficacy, and improve chemical structures. Thus, AI-powered platforms drastically cut discovery time, providing an immense benefit to pharmaceutical businesses.[6] [7] [8]

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Figure 1 Advantages of small-molecule drugs

Small molecules and metals are often employed in therapeutic development as they provide mutual benefits. Small molecules are practical, easy to synthesize, can interact with biological targets, and offer flexibility in delivery. Metals have properties that, when combined with those of small molecules, increase the potential of the latter as therapeutic agents. These characteristics of metals include their abilities to produce reactive oxygen species (ROS) and to display redox activity and coordination. This combination can improve cancer therapies. A hybrid technique combining the chemical and biological properties of metals with the adaptive pharmacokinetic profiles of small molecules expands the scope of medicinal design. Metal-based pharmacophores have changed therapeutic methods in drug development, especially in oncology. Ruthenium, palladium, nickel, and platinum are versatile components in medicines because they target biological processes that organic chemicals cannot, establish unique coordination bonds, catalyze redox activities, and form unique coordination bonds. The ongoing development of metal-based small molecules suggests that ruthenium complexes can have a selective impact on cancer cells while displaying milder side effects than cisplatin, and they have shown promising results.[1] [9] Ruthenium-based complexes have been established for cancer diagnosis and for the treatment of neurological diseases, infections, and inflammation, in addition to their role in oncology. In addition to this, some important actions have also proven to be beneficial, as listed in Table [1].[10–29]

Table 1 Classification of Ruthenium Metal Complexes Based on Their Use

Entry

Category

Examples

Primary action

1

anticancer agents

NAMI-A, KP1019

DNA binding, apoptosis

NKP-1339, IT139

DNA damage, mitochondrial dysfunction

BOLD-100

ROS generation

2

antimicrobial agents

RAPTA, [Ru(phen)2(dppz)]2+

membrane disruption, oxidative stress

3

PDT Agents

TLD1433, Ru(II) polypyridyl

light-induced ROS production

4

antiinflammatory agents

Ruthenium NSAID complexes

targeting of inflammatory mediators

5

diagnostic agents

luminescent Ru complexes

fluorescent imaging of cells and tissue

The use of ruthenium metal in cancer treatment and its development is the primary focus of this Account, which includes a ligand-based classification and a review of the mode of action. Whereas platinum-based drugs, such as cisplatin, laid the groundwork, newer metals, such as ruthenium, have superior targeting and reduced toxicity. Nickel and palladium are also being studied for their electrophilic and catalytic properties, which make them suitable for redox-active processes that improve anticancer drugs. In addition to cell apoptosis, metal pharmacophores can help to construct linker systems and tailored payloads that transport drugs to tumor sites for precise delivery.[30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]. Among metal-linked small compounds, ruthenium complexes are stable, can display various oxidation states, and target cancer cells. Although challenges with Ru metal-based drugs remain, a fully clinical candidate based on Ru metal is expected to appear in the near future.[43–48] This Account emphasizes the potential of ruthenium metal-based pharmacophores to address medical challenges in oncology. In particular, these pharmacophores can increase therapeutic precision, reduce undesirable effects, and offer novel strategies for managing cancer drug resistance. Using the latest data, this Account examines the mechanisms of metal-based medications, their applications, and the prospects for their clinical development in cancer treatment.


# 2

Importance of Ruthenium Metal and Its Complexes

One of the noblest and least-expensive metals, ruthenium was employed in catalytic reactions until replaced by other metals. Significant discoveries in the chemistry of ruthenium were recognized by the award of the Nobel Prize in Chemistry to Robert Grubbs in 2005 and to Ryōji Noyori and William Knowles in 2001.[49] [50] Ruthenium has been used extensively as a catalyst to activate inert C‒H bonds to form unusual aromatic C–C bonds through metal legation.[51,52] Besides its chemical properties, ruthenium has been used in treatment and diagnosis, and its advantageous biological properties are illustrated in Figure [2]. The biological activities of ruthenium compounds are strongly dependent on their ligand structure.[53]

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Figure 2 Uses of ruthenium complexes

Ruthenium complexes were extensively employed as anticancer agents by Sava, Kratz, and their co-workers in the 1990s.[53] [54] These researchers have since developed a series of ruthenium(III) anticancer complexes, some of which are drugs considered for clinical experiments. Those include NAMI-A (antimetastatic), KP-1019, and IT-139. The anticancer agent NKP 1339 is currently undergoing clinical trials. The effectiveness of ruthenium(III) anticancer compounds against certain cisplatin-resistant cell lines, their minimal or nonexistent side effects, and their high water solubility are among their advantages.


# 3

Synthesis of Ruthenium Complexes

Synthesizing and isolating a ruthenium-based lead molecule involves a stepwise approach, from choosing an appropriate ruthenium precursor to ligand coordination and purification. Scheme [1] shows a general procedure for synthesizing and isolating a ruthenium-based complex. A generalized synthetic scheme for ruthenium complexes involves several key steps. First, a ruthenium precursor, such as RuCl3 or a Ru(II) salt (for example, [RuCl₂(PPh₃)₄]) is dissolved in a suitable solvent (e.g., ethanol or methanol). Concurrently, a bidentate ligand (e.g., 2,2′-bipyridine or phenanthroline) is dissolved in the same or a different solvent. The two solutions are then mixed, and the mixture is heated under reflux (typically at 60–100 °C) for several hours to facilitate complex formation. After cooling, the complex is precipitated by adding a nonsolvent (e.g., diethyl ether), followed by vacuum filtration to collect the solid. The precipitate is washed with cold solvent to remove unreacted components and then dried under a vacuum, followed by characterization of the complex.[55] [56] [57] [58]

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Scheme 1 Step-by-step synthesis of ruthenium-based lead molecules

# 4

Classification of Ruthenium Complex Antitumor Drugs Based on their Mode of Action

Ruthenium-based drugs exhibit significant activities inside the body because several key factors contribute to their therapeutic effectiveness, particularly in oncology, as described in Table [2]. Ruthenium-based drugs exhibit significant therapeutic activity in oncology because several vital factors, such as their unique coordination chemistry, allow them to form stable complexes with biological macromolecules.[12]

Table 2 Pharmacological Classification of Antitumor Ru Metal Complexes

Entry

Mode of action

Name/class of drug

References for mode of action

1

Generation of ROS through redox reaction, which contributes to cytotoxic effects through excessive oxidative stress

TLD-1433

[59]

2

Targeting mitochondria to release cytochrome c to induce cell death

Ru II (β-carboline), KP 1339. IT 139

[60]

3

DNA binding and damage

NAMI-A, NKP-1339, RAPTA C

[61]

4

Transferrin ruthenium complex formation and enhancement of influx of Ru

KP-1090

[62]

5

Epidermal growth factor receptor inhibition for cancer death

Ruthenium(II) polypyridyl complexes,

[63]

6

Cell apoptosis through G0/G1 cell cycle arrest

Asymmetric ruthenium(II) complexes, RM 175

[64]

7

Photodynamic therapy by activating cancer cells and production of ROS

Ru(II)/Ir(III)/Re(I)-based complexes, RAPTA-A, ruthenium polypyridyl complexes.

[65]

8

Fibroblast growth factor receptor (FGFR) inhibitor

Ruthenium cyclopentadienyl–peptide conjugate complexes

[66]

The ability of ruthenium complexes to selectively deliver therapeutic agents to cancer cells while minimizing systemic toxicity highlights their potential for improving treatment outcomes in oncology. Ruthenium remains a topic of interest because of its various advantages, and future work related to cancer is still needed to explore safer ligands with targeted actions. Many ruthenium complexes, such as NAMI-A and RAPTA-C, cause cell death through multitarget systems, so a pharmacological classification does not provide significant classes and subclasses. Consequently, a chemistry-based classification is needed for better representation of ruthenium complexes.


# 5

Classification of Ruthenium Complex Antitumor Drugs Based on their Structure and the Oxidation State of Ruthenium

5.1

Ruthenium(III) with DMSO

The octahedral geometry of the hexacoordinate structure of ruthenium(III) offers diverse synthetic possibilities. It opens up opportunities for the conjugation of pharmacophores to create a variety of multitarget ruthenium complexes. Examples include derivatives of 4-anilinoquinolines such as gefitinib, which inhibits epidermal growth factor receptor (EFGR) and stops the proliferation of cancerous cells that overexpress EGFR. Nevertheless, it is still unclear which moiety of the molecules should be conjugated with other molecules to form a multitargeting anticancer drug agent without interfering with the ability of EGFR to interact with the target receptor. To overcome these problems, several complexes of Ru(III) with dimethyl sulfoxide (DMSO) that are suitable as anticancer drugs have been created. These complexes were created by conjugation of 4-anilinoquinazoline derivatives.[67] [68] [69] Ruthenium azopyridine complexes are significant and promising organometallic compounds because of their high activities and extremely low toxicities in comparison to other metals, such as platinum. They were created by combining a ruthenium(III)–DMSO moiety with 6-methoxy groups on quinazolines. The ligand structure mainly governs the biological characteristics of ruthenium-containing drugs.[70–73] Ruthenium-based drug molecules, such as NKP-1339, represent a new class of anticancer agents with high therapeutic potential. The ability of these compounds to target cancer cells selectively, cause damage to DNA, and induce apoptosis, while maintaining a favorable toxicity profile, makes them excellent candidates for further development in oncology.[74,75]


# 5.2

Ruthenium Complexes with Polypyridine

Low micromolar concentrations of polypyridine–Ru(II) complexes displayed an antiproliferative effect in an MTT assay with the cell lines Melanoma B16, Hep-G2, A549 carcinoma, and LO2 normal.[75] In terms of their selectivity and antiproliferative effects, the compounds outperformed cisplatin, particularly against the B16 cell line. Apoptosis was elevated, the G0/G1 cell cycle was arrested, and cell migration was disrupted. Moreover, the level of intracellular ROS significantly increased in B16 cells. The mitochondrial membrane was breached by the Ru(II) complexes. Upon comparing an experimental group that received treatment with a control group that remained untreated, a noteworthy reduction in the level of intracellular glutathione was observed alongside an increase in the level of malondialdehyde.[76] A polypyridyl Ru(II) complex containing a naphthoquinone moiety, specifically plumbagin, has been successfully synthesized.[77] The two most potent complexes contain plumbagin and 1,10-phenanthroline or 4,7-diphenyl-1,10-phenanthroline. An enhancement of biological activity toward the in vivo MCG-803 tumor mouse model was observed when the lipophilicity level of the additional ligands was increased, transitioning from DMSO, bipyridine, and 1,10-phenanthroline to 4,7-diphenyl-1,10-phenanthroline. The two most efficacious compounds elicited G0/G1 arrest in the cell cycle through pronounced inhibition of mitochondrial respiration and glycolysis, induction of DNA damage, and augmentation of the activity of cell-growth arrest, in addition to damage to the DNA-activated alpha (GADD45A) gene.

Notaro and colleagues conducted a study on a Ru(II) complex containing polypyridyl ligands and a maltol (3-hydroxy-2-methyl-4H-pyran-4-one) ligand, prepared by the procedure shown in Scheme [2]; the presence of the maltol ligand led to an increase in the bioavailability of the metal.[78] An absence of discernible selective toxicity toward cancer cells was observed, as the compound exhibited potent cytotoxicity against various cell types, including HeLa and A2780 cancer cells and their cisplatin- and doxorubicin-resistant variants (A2780cis and A2780ADR), in addition to normal RPE-1 cells. The cytotoxicity of the complex was enhanced by the addition of the maltol moiety (IC50 = 0.42–2.86 μM) despite the inherent lack of toxicity of maltol. After four hours in an incubation setting, more-significant cellular accumulation was observed compared with the effects induced by cisplatin. This outcome indicated that the compound in question elicits apoptosis in HeLa cells.

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Scheme 2 Synthesis of Ru(II) complex containing polypyridyl and a maltol ligand

The cellular nucleus serves as the primary site for accumulating cellular components. A separate investigation revealed that ABCB1 export, in conjunction with EGFR gene expression, plays a pivotal role in conferring cellular resistance to ruthenium-containing compounds.[79] Biological efficacy is enhanced by inhibition of these genetic elements. The efficacy of coadministration of taxol and a Ru(II) polypyridyl complex that inherently exhibits antiproliferative properties was investigated by Chen et al.[80] using taxol-resistant derivatives of the HeLa and A549 cell lines. Even when the ruthenium compound was administered in minimal quantities, synergistic effects were observed, ROS levels increased, gasdermin D (GSDMD) was activated, and the HeLa/Taxol cells underwent pyroptosis.


# 5.3

Ruthenium Complexes with p-Cymene

Ruthenium(II) complexes containing p-cymene and imidazophenanthroline ligands, synthesized by the method shown in Scheme [3], were tested for their cytotoxic action against HeLa, CaCo-2, and HEK-293 cell lines.[81]

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Scheme 3 Synthesis of Ru(II) complexes containing p-cymene and imidazophenanthroline ligands

The compounds were found to bind to bovine serum albumin (BSA) and CT-DNA. Compound 1 (Figure [3]) showed an antiproliferative efficacy (IC50 = 2.0–2.5 μM) in an MTT assay. A minimal toxic effect toward HEK293 cells was exhibited, as evidenced by a selectivity factor in excess of 40.

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Figure 3 Ru complex with p-cymene

Significant antiproliferative efficacy was observed, even at concentrations as high as 1 mM of glutathione. The decrease in activity was negligible. Whereas the addition of electron-withdrawing groups increased the cytotoxicity, adding electron-donating groups decreased the biological activity of the hydroxyphenyl moiety.

The efficacy of analogous complexes featuring phenyl groups substituted with other than hydroxyphenyl moieties was assessed for malignant MDB-MA-231 and HeLa cell lines, and the regular HEK293 cell line.[82] Binding to CT-DNA and BSA were observed. The antiproliferative efficacy of two of these compounds toward cancer cells, as determined by an MTT assay, resembled that of cisplatin. However, their deleterious impact on the standard cell line was notably lower, as evidenced by IC50 values of 85 and 178 μM, in contrast to the value of 64 μM for cisplatin. Incorporation of a p-fluorophenyl moiety resulted in enhanced efficacy against HeLa cells, whereas including a p-nitrophenyl moiety led to increased toxicity toward MDB-MA-231 cells.

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Scheme 4 Synthesis of bisaminophosphine complexes of ruthenium(II) with a p-cymene ligand

It has been discovered that the two bisaminophosphine complexes of ruthenium(II) with p-cymene ligands 2 and 3 (Scheme [4]) significantly inhibit the proliferation of A375 cells.[83] The synthesis of the complexes was optimized and finalized for better yields. These complexes have IC50 values of 6.72 and 8.76 μM, respectively, which are lower than that of cisplatin. Both substances showed higher activities than the bisaminophosphine ligand alone.

A complex mixture that included two p-cymene–Ru(II) units caused cell death in the lines under investigation. When evaluated against the OVCAR-3, M-14, and HOP-62 malignant cell lines, several Ru(II)–p-cymene complexes with cyclic/polycyclic aromatic diamine ligands showed better lethal effects than cisplatin, with IC50 values ranging from 4.31 to 6.31 μM.[84] CT-DNA binding improved with greater delocalization of the aromatic component of the ligand. Nuclear p-cymene–tetrazole–Ru(II) complexes were used to conduct MTT experiments on several cancer cell lines.[85] The ligands, on their own, showed no cytotoxicity. Two of the compounds were successfully used to kill HeLa, MCF-7, and A549 cell lines. DNA binding, bovine serum albumin binding, and the finding of morphological changes indicative of apoptosis were among the experimental findings. Cell migration and the advancement of the cell cycle were stopped during the G0/G1 phase.

Several Ru(II)–arene complexes with N-heterocyclic carbenes have been synthesized and evaluated for their antiproliferative effects (Figure [4]).[86] An MTT assay revealed that a very low cytotoxicity after 48 hours of exposure was produced by attaching short alkyl moieties. For a panel of cancer cell lines including A549, HT-29, HCT116, LoVo, HeLa, and A2780, complexes 4 and 5 displayed the highest lipophilicity and exhibited a greater cytotoxicity than cisplatin (IC50 = 1.98–25.6 μM). These compounds induce mitochondrial dysfunction and intracellular ROS production, and their effects on A2780 cells include antimigratory and proapoptotic effects.

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Figure 4 Ru complexes with p-cymene described by Alkış et al.[87]

Ru(II) complexes containing Schiff bases and p-cymene were effective against Caco-2 and L-929 normal mouse fibroblasts.[88] The ruthenium complex of the Schiff ligand, which was the less toxic of the two (IC50 = 803.65 μM; ligand alone: IC50 = 510.26 μM), showed only a modest antiproliferative activity against Caco-2 cells.


# 5.4

Ruthenium Azopyridine Complexes

Azopyridine ligands for ruthenium compound (Figure [5]) are organic components in which a pyridine component and an aromatic ring are linked by an azo bond that provides photochemical activity[89] and can bind with a ruthenium ion, resulting in redox reduction of the metal along with a decisive stability factor.[90] These complexes have potent anticancer properties. The reported activities are mainly against breast cancer (MCF-7), renal cancer, ovarian cancer, lung cancer, and colon cancer. The compounds are highly active, have shown encouraging results, and are less poisonous than platinum. The ligand structure of these complexes profoundly influences their biological characteristics.[91]

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Figure 5 Ruthenium azopyridine complexes. X2 = H, H, and CH3; X1 = 2-phenylazopyridine, o-tolylazopyridine, and 4-methyl-2-phenylazopyridine, respectively.

# 5.5

Ruthenium Polypyridyl Complexes

Another group of ruthenium complexes, the ruthenium polypyridyl complexes, are vital in several applications, such as dye-sensitized solar cells[92] [93], and have potential chemical effects, for example in photodynamic therapy.[94] The complexes formed between the ligands and ruthenium give rise to cations that undergo noncovalent and reversible interactions with DNA.[95] Metal-to-ligand charge transfer (MLCT) is responsible for the visible-light absorption in ruthenium polypyridyl complexes, especially at about 450 nm. Long-lived excited states with the ability to interact with nucleic acids are created as a consequence of this process. Due to these interactions, ruthenium complexes are interesting candidates for applications involving photodynamic therapy, in which the compounds are activated by light in targeted cancer cells to produce ROS, which can lead to cell death (Figure [6]). Because these complexes can target cancer cells specifically while causing minor damage to healthy tissues, their creation has attracted much attention and should be helpful for therapeutic applications.[96]

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Figure 6 Photodynamic therapy for the cancer-cell death

Several studies have demonstrated that ruthenium-based compounds can selectively bind to G-quadruplex (G4) DNA structures, which are highly relevant in cancer biology. This binding to G4 sites suggests that ruthenium complexes hold significant promise as anticancer agents, especially compared with the platinum-based drugs currently in clinical use. Due to their unique mechanism of action, which involves DNA interactions and reduced toxicity to healthy cells, ruthenium complexes are emerging as superior alternatives to traditional platinum-based chemotherapies.[97] [98] Ruthenium-based G-4 binders have been reported that incorporate an inert polypyridyl complex (for example, see Figure [7]), one of which is an N,N-ligand that has an enhanced aromatic moiety that allows partial stacking along with the G4 tetrads. These complexes are extensively used as anticancer agents.[99,100] Other reported ruthenium complexes incorporate phenanthrol–imidazole ligands that increase the stability of G-quadruplex structures, particularly in the c-Myc oncogene, through a groove-binding mechanism. These complexes can act as specific anticancer agents because it is known that they prevent breast cancer cells from proliferating, migrating, and invading.[101]

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Figure 7 A Ru complex with polypyridine ligands

An anthraquinone and ruthenium polypyridyl complex is lipophilic and capable of penetrating lysosomes. In the absence of light, the complex halts the production of intracellular ROS. However, when cells are exposed to light, the generation of intracellular ROS is significantly increased. Cytotoxicity MTT assays were conducted on various cell lines, including regular liver cell lines (LO2), a breast cancer cell line (MCF-7), a lung cancer cell line (A549), the NB-4 leukemia cell line (A2780), and the cisplatin-resistant A2780R line. After a 48-hour incubation period under low-light conditions, all the cell lines presented IC50 values within the moderate range of 35–250 μM. Remarkably, a brief 15-minute stimulus with light led to a significant increase in cytotoxicity, as demonstrated by a reduction in the IC50 values from 35 to 25 μM. All the cell lines had phototoxicity indices of between 4 and 28.5 μM. According to Kumar and Nair, the primary mechanism by which these cells react to light exposure is the start of autophagy.[78] [102]


# 5.6

Cyclometallic Ruthenium Compounds

Cyclometalated ruthenium compounds are promising alternatives to platinum-based chemotherapeutics, and exhibit potent anticancer activity. These ruthenium complexes offer several advantages, including improved selectivity toward cancer cells, reduced side effects, and overcoming of the drug resistance often associated with platinum compounds.[103] Several methods have been developed to improve the cytotoxicity and modes of action of these cyclometalated drugs.[104] Ruthenium cyclometalation enhances complex stability and reactivity. The chemicals interact efficiently with biomolecules such as DNA in killing cancer cells. The cytotoxic characteristics and structure–activity relationships for cyclometalated ruthenium compounds are shown in Figure [8], along with design methods.[105]

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Figure 8 Ruthenium-based anticancer drugs display a variety of mechanisms (X = leaving group; Ln = strongly bound ligands)

In recent studies, specific modifications to ligands and metal centers have been explored to improve binding affinity to DNA and to enhance anticancer efficacy. For example, the introduction of various substituents on ligands has been shown to significantly influence the biological activity of these compounds, making them highly effective in targeting various types of cancer.[106]


#
# 6

Current Status of Drug Clinical Trials[107]

BOLD-100 is currently undergoing a Phase 1b/2 clinical trial (NCT04421820) to assess its safety and efficacy when combined with the FOLFOX chemotherapy regimen for patients with advanced gastrointestinal cancers, including colorectal, gastric, bile duct, and pancreatic cancers. The trial began in 2020 and is projected to continue until 2026.[108]

NKP-1339 is currently undergoing clinical evaluation and it completed Phase 1 trials in 2012. The drug has mild side effects and is active in patients with advanced refractory cancers. It has been identified as a promising candidate for further studies, including combination therapies and Phase II trials.[109]


# 7

Status and Applications of Metals Other than Ruthenium

In addition to ruthenium, some complexes of other metals, such as rhodium, palladium platinum, zinc, cadmium, and mercury, have also been tested. Each contributes distinct biological activities due to its interactions with biomolecules.

Zinc, an essential metal, often coordinates with Schiff bases and thiosemicarbazones to exhibit antimicrobial effects against pathogens such as Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.[110] Cadmium is notable for its anticancer action, primarily through DNA mismatch-repair inhibition, and its antimicrobial effects on fungi and bacteria. Mercury complexes, particularly those with thiosemicarbazones, display potent antiamoebic and antimicrobial properties. The potential of these metal complexes in therapeutic applications continues to be actively investigated.

Cadmium is hazardous in high doses, yet its ability to block DNA repair pathways makes it useful in cancer treatment. Stopping DNA mismatch repair causes mutations and cancer cell death. The preferential toxicity of cadmium toward cancer cells makes it an intriguing therapeutic target.[111] Cadmium complexes containing thiosemicarbazones also show broad-spectrum antibacterial activity, even toward drug-resistant species. Cadmium complexes are, therefore, promising antibacterial and anticancer drugs, but dosage monitoring is necessary to reduce their toxicity.[112]

Mercury(II) complexes, notably those containing thiosemicarbazones, are antibacterial and antiparasitic and can attack Entamoeba histolytica, E. coli, S. aureus, and P. aeruginosa. Mercury complexes inhibit pathogen metabolism by binding to microbial proteins. Mercury thiosemicarbazone complexes have also been studied for their anticancer properties, increasing their medicinal potential. Because mercury is toxic, these complexes must maintain safety and effectiveness to avoid side effects in medicinal applications.[113] [114]


# 8

Conclusion

A comprehensive exploration of ruthenium and its applications in biological sciences reveals that the metal’s oxidation states and specific ligands play pivotal roles in determining its mechanism of action, selectivity, and therapeutic efficacy. This is especially evident in its interactions with cancer cells, where these factors contribute to its targeted biological activity and potential as a cancer-treatment agent. Research findings underscore the importance of ligand coordination and oxidation-state modulation in optimizing the biological performance of ruthenium-based compounds. The current advances in ruthenium-based therapeutic agents emphasize the promising future of this metal when small molecules are combined into its core structure. Such amalgamation has been instrumental in enhancing the pharmacological properties of ruthenium complexes, particularly their potential as anticancer agents. However, the clinical progress of these compounds has encountered challenges. For instance, despite its initial promise, NAMI-A failed to successfully pass clinical trials, largely due to limitations in its efficacy, and its toxicity profile. In contrast, other ruthenium-based candidates, such as BOLD-100 (formerly known as KP1019) and NKP-1339, have demonstrated significant promise and are currently undergoing clinical evaluation. Both compounds exhibit high potential for selective targeting of cancer cells while maintaining lower toxicity levels compared with conventional chemotherapeutics. The ongoing clinical trials inspire optimism regarding the potential of ruthenium complexes to achieve regulatory approval and establish a new class of metal-based therapeutics with improved specificity and safety. This trajectory highlights the need for continued research into the interplay between small molecules and ruthenium’s core chemistry to unlock its full potential in medicine.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

All authors would like to express their sincere gratitude to their respective universities for their unwavering support throughout this research.

Declaration of GenAI use: During the writing process of this paper, the author (s) used Chat GPT to design figure 6. The authors reviewed and edited the text and take full responsibility for the content of the paper.


Corresponding Author

Priyank Purohit
Himalayan Institute of Pharmaceutical Science
SRHU, Jolly Grant Swami Ram Nagar, beside Jolly Grant Airport, Dehradun, Uttarakhand 248016
India   

Publication History

Received: 06 October 2024

Accepted after revision: 11 December 2024

Article published online:
06 March 2025

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Figure 1 Advantages of small-molecule drugs
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Figure 2 Uses of ruthenium complexes
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Scheme 1 Step-by-step synthesis of ruthenium-based lead molecules
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Scheme 2 Synthesis of Ru(II) complex containing polypyridyl and a maltol ligand
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Scheme 3 Synthesis of Ru(II) complexes containing p-cymene and imidazophenanthroline ligands
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Figure 3 Ru complex with p-cymene
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Scheme 4 Synthesis of bisaminophosphine complexes of ruthenium(II) with a p-cymene ligand
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Figure 4 Ru complexes with p-cymene described by Alkış et al.[87]
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Figure 5 Ruthenium azopyridine complexes. X2 = H, H, and CH3; X1 = 2-phenylazopyridine, o-tolylazopyridine, and 4-methyl-2-phenylazopyridine, respectively.
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Figure 6 Photodynamic therapy for the cancer-cell death
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Figure 7 A Ru complex with polypyridine ligands
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Figure 8 Ruthenium-based anticancer drugs display a variety of mechanisms (X = leaving group; Ln = strongly bound ligands)