Exploring the synthesis of Ru(II)/Ir(III)/Re(I)/Rh(III)-based complexes as anticancer metallopharmaceuticals: significance, challenges and future perspective

Abstract

Metal complexes exhibit significant potential in the field of anticancer metallotherapeutics due to their high selectivity toward cancer cells and their effectiveness in targeted drug delivery. This frontier article summarizes recent advances in the synthesis of mono-, bi-, and mixed-metallic Ru(II)/Ir(III)/Re(I)/Rh(III) complexes for anticancer applications. Additionally, various therapeutic approaches and their mechanisms of action in Ru(II)/Ir(III)/Re(I)/Rh(III)-based complexes are discussed. In this study, we provide insights into the contributions of various research groups toward the development of transition metal complexes with promising therapeutic potential. This study also addresses the challenges encountered throughout the designing and application process as well as the future perspectives of these metallopharmaceuticals.

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Sreelekha U

Sreelekha U received her Bachelor of Science degree from the Government College Madappally, University of Calicut, India, in 2019 and her Master of Science degree in Chemistry from the Central University of Kerala, India, in 2021. She is currently pursuing her PhD under the guidance of Dr Priyankar Paira at Vellore Institute of Technology, Vellore, India. Her research interest includes Organometallic and Bioinorganic Chemistry.

Rinku Chakrabarty

Dr Rinku Chakrabarty embarked on her academic journey in 2011 at IIEST, Shibpur, India, where she pursued her Ph.D. in Supramolecular Chemistry under the guidance of Prof. Shyamaprosad Goswami. She later undertook postdoctoral research at the University of Witwatersrand, Johannesburg, South Africa, focusing on the synthesis of rare-earth-based molecular systems for use as MRI agents. Her passion for academia led her to assume the role of an Assistant Professor in the Department of Chemistry at Alipurduar University. Her research interests include nanomaterials, molecular sensing and bioinorganic chemistry, reflecting her unwavering commitment to advancing the field of Chemistry.

Priyankar Paira

Dr Priyankar Paira, MRSC, is an Associate Professor at VIT, Vellore, Tamil Nadu, India. He received his Ph.D. from the Indian Institute of Chemical Biology (IICB), Jadavpur University, Kolkata, and completed his postdoctoral research at the National University of Singapore under the supervision of Prof. Giorgia Pastorin and Prof. Ang Wee Han. He is a Bioinorganic and Medicinal Chemist with 12 years of experience. He has published more than 100 articles in reputed international journals, with over 2634 citations and an h-index of 28. He also holds three patents in Medicinal Chemistry. He has completed three DST projects, two ICMR projects and is currently working on a CSIR project. He is associated with professional bodies such as ACS, RSC and SBIC.

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Introduction

Cancer is the most critical chronic disease and the second leading cause of death worldwide, following heart disease.¹ Some primary causes of cancer include metastasis, uncontrolled proliferation, confrontation to apoptosis, infection, organ damage, blood cell issues, etc.² Chemotherapy, radiation therapy, and surgery are the main treatment strategies to get rid of this menace. In 1965, Barnett Rosenberg³ opened the door to a new era of metal complexes with the serendipitous discovery of cisplatin, which would be used in cancer therapy, heralding the beginning of modern inorganic medicinal chemistry. This stupendous discovery has some major side effects and drawbacks like lack of selectivity, drug resistance, and serious toxicity,^4,5 which make the treatment procedure of cancer a challenging work. Therefore, the development of non-platinum metallodrugs,⁶ particularly Ru(II)/Ir(III)/Re(I)/Rh(III)-based complexes,^7–10 has attracted significant interest over the past few decades for their potential as anticancer metallopharmaceuticals.

Ru is a transition metal belonging to group VIII of the periodic table and commonly exhibits two oxidation states, +2 and +3, which may exist in other less common oxidation states (+4, +6, and +8) depending on the chemical environment. Under the pH of cancer cells, Ru(III) is reduced to its more active form Ru(II).¹¹ The first Ru(III) complex NAMI-A paved the way to enter the phase-1 clinical trial, which failed to pass the phase-2 trial due to some therapeutic constraints. The discovery of another Ru(III) complex, KP1019, by the Keppler group for clinical trial started the development in this field, followed by a further modified complex, KP1339,¹¹ which is currently recognized as BOLD-100. The photoactive Ru(II) complex TLD1433 is considered another milestone that passed clinical trial phase-1 for the treatment of bladder cancer.^12–14

Ir(III) complexes, characterized by low spin, kinetic inertness and high stability, exhibit properties comparable to those of Ru(II) complexes. They are known for their remarkable quantum yields, substantial Stokes shifts, long emission lifetimes, catalytic activity, and flexible coordination geometry. Additionally, Ir(III) complexes are highly photostable and exhibit relatively low toxicity, with their stability contributing to minimal off-target effects in tumor microenvironments. Their excellent cellular permeability, pronounced redox characteristics, and effective ligand exchange capabilities further enhance their potential as promising candidates for anticancer therapy.^15,16

Rhenium possesses several oxidation states, viz. +1, +2, +3, +4, +5, +6, +7, −1 and −3. Re(I) complexes are highly photostable, and their photodynamic properties are noteworthy. Redox-active tricarbonyl complexes of Re(I) exhibit a high quantum yield, large Stokes shift and significant luminescent lifetime.^17,18 Noble and rare metal, rhenium, has important applications in the fields of catalysis and medicinal chemistry. Most rhodium complexes are in the preclinical stage and have not yet been extensively tested in clinical trials.

Ru(II)/Ir(III)/Re(I)/Rh(III)-based complexes were designed to maximize their anticancer efficacy by incorporating the following key features: (a) inherent biological activity, (b) efficient towards cancer cell environment (hypoxic, high GSH, low pH), (c) extended π-conjugation to enhance fluorescent properties for bioimaging, (d) hydrophobic moieties that improve cellular accumulation by enhancing membrane permeability and intracellular uptake, and (e) strong interaction with DNA (Fig. 1). Cancer cells tend to overexpress glutathione (GSH) and elevate the reduced state of adenine dinucleotide phosphate (NADPH) production to counteract oxidative stress because NADPH plays a key role in regenerating GSH from its oxidized form (GSSG) via glutathione reductase. Targeting this redox buffering system – either by depleting GSH or inhibiting NADPH regeneration – has emerged as an effective anticancer strategy. Additionally, the reduced state of nicotinamide adenine dinucleotide (NADH) contributes to redox homeostasis by regulating the NAD⁺/NADH. High levels of reactive oxygen species (ROS) generated by the complex can oxidize NADH, disrupting the redox balance and ultimately inducing cancer cell death.

Fig. 1 Design of Ru(II)/Ir(III)/Re(I)/Rh(III)-based complexes as anticancer metallopharmaceuticals.

In this perspective, we highlight recent advances in the synthesis of monometallic, dimetallic and mixed metallic Ru(II)/Ir(III)/Re(I)/Rh(III) based complexes, discuss their significance, address related challenges, and explore future directions in the field.

Significance and challenges of monometallic complexes in cancer therapy

Ru(II) metalopharmaceuticals

Ruthenium complexes exhibit high solubility in water, whereas the ligand exchange rate in aqueous solution is relatively slow. These complexes also exhibit high activity towards cisplatin resistant cells and low toxicity compared with commonly used anticancer drugs. One crucial property of Ru(II) complexes is that they can bind with the biological molecules present in blood plasma, e.g. albumin, transferrin, etc. like iron. Therefore, the transportation process of the Ru(II) complexes to cancer cells is facilitated with negligible side effects. The high water tolerance property of these complexes makes them the best possible alternatives to anticancer agents.^19,20 The incorporation of arene moieties having extended π conjugation is an excellent idea for maintaining the hydrophilicity and lipophilicity of the Ru(II) complexes.^21,22 These complexes are commonly referred to as half-sandwich complexes, which are important innovations and play a key role in modern drug discovery. In these complexes, the η⁶ arene moiety serves as the seat, with the remaining three positions occupied by ligands, resulting in a piano-stool geometry. One labile leaving group, typically a chloride (–Cl), is included, and together with two ligands, it forms the legs of the stool.

For the synthesis of Ru(II)-based complexes as anticancer metallopharmaceuticals, researchers have focused on incorporating ligands with nitrogen (N) and phosphorus (P) donor atoms. In this regard, bipyridine, phenanthroline, etc. ligands are a common choice. Synthesis is initiated with a suitable Ru precursor and the corresponding ligand to achieve the desired product with stability and biological activity towards cancer cell lines. The biological activity and cancer cell targeting specificity of the synthesized complexes can be tuned by altering the ligand structure.

Furoyl thiourea ligand was introduced by Dorairaj et al. (1) into Ru(II) metal to act as an anticancer agent for the breast cancer cell lines MDA-MB-231, T47-D, and MCF-7. Their studies have shown that the introduction of Ru metal increases its activity. The incorporation of the PPh₃ group also increases the potentiality of the complexes. In vivo studies have also been performed with significant results.²³ Khater et al.²⁴ synthesized two Ru(II) flavone complexes (2), studied their potency against two breast cancer cell lines, MCF-7 and MDA-MB-231, and found significantly improved activity. Non-intercalative interactions were observed between the c-myc i-motif and VEGF DNA sequences. Varieties of ligands have been incorporated into Ru metal for complex formation by Antonets et al. (3),²⁵ Sahu et al. (4),²⁶ Qi et al. (5),²⁷ Marco et al. (6),²⁸ and Abad-Montero et al. (30).²⁹

Low solubility, marginal stability, and low cellular uptake are the main challenges of Ru-based complexes as anticancer agents. Low aqueous solubility, short half-life in in vivo method, and short circulation time pose significant challenges in clinical applications. Therefore, intravenous injection remains the only viable administration route, leading to low bioavailability and reduced accumulation in target tumor cells. Numerous researchers have adapted various approaches to address these challenges. One of the most effective approaches is the introduction of nanosystems into drug delivery due to their stability, solubility, and sustainable release of drugs into the target organ.^30–32

Ir(III) metalopharmaceuticals

Recently, there has been growing interest among researchers in the strategic design and synthesis of iridium(III) complexes due to their exceptional photoluminescent properties and promising anticancer activity. Naphthacene-based ligand (7) was introduced by Gonzalo-Navarro et al. for application in photodynamic therapy (PDT). Light-driven antiproliferative activity was studied extensively under dark conditions. π-Expansive ligands were used for designing the ligand.³³ Phenanthroline based naphthalene diimide ligand (8), was used by Yang et al.³⁴ in the synthesis of Ir complexes, and their effects on hypoxic tumors were investigated. In vitro studies were conducted in detail for phototoxicity under hypoxic and normoxic conditions. In vivo studies performed after laser activation of tumor cells show excellent results.

Das et al. reported an imidazole-based quinoline-containing PTA complex (9) and studied its activity in the presence of GSH against the MDA-MB-231 cell line and found an excellent result, with an IC₅₀ value of 2.8 μM.³⁵ Extensive studies have demonstrated that the reported compound functions as a highly selective and hypoxia-effective metallodrug for the treatment of triple-negative breast cancer. He et al. designed and synthesized a 4,7-dichloro-1,10-phenanthroline-based iridium complex (10). Among the three potent complexes, the one with the highest lipophilicity demonstrated the strongest anticancer activity against HeLa cells, with an IC₅₀ value of 0.83 μM. This compound also exhibited significant tumor growth inhibition in in vivo experiments in a mouse xenograft tumor model.³⁶ A diverse library of compounds has been developed by researchers in the quest for innovative anticancer metallodrugs. Notably, Pivovarova et al. (11),³⁷ Kowalik et al. (12),³⁸ Ramos et al. (13),³⁹ Chu et al. (14),⁴⁰ Łomzik et al. (15),⁴¹ Negi et al. (34),⁴² Ortega-Forte et al. (35),⁴³ and Linero-Artiaga et al. (36)⁴⁴ have introduced various ligands for the complexation of Ir complexes.

Re(I) metalopharmaceuticals

Naphthyl-based Re complexes were designed by Darshani et al.⁴⁵ and studied their in vitro cytotoxic activity using non-small cell lung cancer cells, NCI-H292, and normal lung cell line MRC-5. Compound 16 exhibited the highest cytotoxicity (IC₅₀ = 9.91 μM) and may be a potent drug for lung cancer. Aminoquinoline-based ligands (17) were introduced by Zinman et al. and used against the hormone-dependent breast cancer cell line MCF-7 and hormone-independent breast cancer cell line MDA-MB-231. The synthesized compound was three-fold more active than the common drug, cisplatin. The binding affinity of the synthesized complexes with calf thymus DNA and bovine serum albumin was excellent and was supported by in silico studies.⁴⁶

Kushwaha et al. synthesized three Re(I) complexes (18) and compared the effectiveness of photoactivated cancer therapy and sonodynamic therapy (SDT). The rhenium complex attached with the –NO₂ group exhibited no cytotoxicity upon ultrasound exposure, whereas the complex with the –NH₂ group demonstrated cytotoxic effects against HeLa cells.⁴⁷ The IC₅₀ values were calculated to be 2 μM and 5 μM under light and sound exposure, respectively. Kushwaha et al. and Marco et al. introduced a new class of ligands for the synthesis of Re complexes with potential anticancer activity (19, 20). Interesting results have been studied by the researchers upon the incorporation of different ligands in designing Re complexes by Kushwaha et al. (19)⁴⁸ and Marco et al. (20).⁴⁹

Rh(III) metalopharmaceuticals

Two isoquinoline-based Rh(III) complexes were designed and synthesized by Khan et al. The anticancer potency of these complexes was extensively studied and demonstrated promising results towards T24 cell lines. These complexes induce apoptosis through mitochondrial dysfunction and arrest the cell cycle in the S-phase. In vivo studies were performed in the T-24 xenograft mouse model, and the synthesized Rh complex 21, exhibited inhibition towards tumor growth. The in vivo safety profile of one Rh complex is better than that of the commonly used drug cisplatin.⁵⁰

A series of picolinamide-based Rh complexes were synthesized by Gu et al., among which two emerged as the most effective candidates against the tested cancer cell lines. These complexes possess high antiproliferative properties via different modes of action, viz. apoptosis, autophagy, and cell cycle arrest. These Rh complexes (22) inhibited the growth of breast and bladder cancer cell metastasis in the xenograft model.⁵¹ In the continuous search for new ligands for the preparation of Rh complexes, Josa et al. (23),⁵² Wei et al. (24),⁵³ and Sink et al. (25)⁵⁴ introduced ligand varieties for synthesizing new Rh complexes with potential anticancer activity.

Significance and challenges of multinuclear complexes as anticancer agents

The application of multinuclear metal complexes has garnered attention from researchers because of their high potentiality and greater degree of selectivity compared to that of their mononuclear congeners. Notably, the platinum-based trinuclear complex also known as triplatin, BBR3464, is a revolutionary breakthrough that still propagates biostability and reduced activity in a phase II trial.⁵⁵

A series of cationic dinuclear Ru para-cymene complexes were reported by Dyson et al. They used thiolato bridges with different substituents. These dinuclear ruthenium complexes were found to be more active towards breast cancer cell line, A270. Studies were also conducted against cisplatin-resistant A2780cisR in the nanomolar range. Compound 26 was claimed to be the most potent one, having the highest toxicity and lowest IC₅₀ values, making it the most cytotoxic one.⁵⁶ Six dinuclear Ir complexes were synthesized by Sheldrick et al. by varying the bridging ligands and were studied against the cell lines MCF-7 and HT-29. Two compounds (27) exhibited the lowest IC₅₀ values (<5 μM). Moreover, they exhibited strong DNA intercalation properties.⁵⁷

Novel metallocyclophanes (28) were reported by Manimaran et al., and extensive biological studies revealed that the latter compound displayed superior activity across various cancer cell lines. The activity of the former one was found to be better against HepG2 cell lines (IC₅₀ value 14.2 μM). On the other hand, the latter one was found to show its activity against HeLa cells (IC₅₀ value 12.8 μM). IC₅₀ values reveal the better activity of these complexes compared with that of cisplatin.⁵⁸ Diastereomeric dinuclear Re(I) complexes (29) containing chiral ligand pynene-bipyridine moiety were developed by Solea et al. The research group has demonstrated a clear relationship between stereochemistry and the biological activity of these complexes. Among all stereoisomers, the diastereomer of compound 30 exhibited exceptional cytotoxicity results against the colon and breast cancer cell lines tested (HCT116 and MCF-7).⁵⁹

Roy et al. synthesized cyclometalated and half-sandwich multinuclear complexes (31) for chemodynamic therapy (CDT), a novel tumor treatment strategy coined by Bu et al., generates ROS through Fenton or Fenton-like reactions in the tumor microenvironment and, unlike PDT, operates without the need for light activation. These complexes follow a novel sialic acid-targeted chemotherapeutic strategy in triple-negative breast cancer cells. Among the complexes, the dinuclear iridium complex showed its potency as a ferroptosis inducer.⁶⁰ Tang et al. synthesized novel dinuclear Ir(III) complex nanoparticles (33) for sonodynamic therapy.⁶¹ Upon ultrasound irradiation, this complex nanoparticle generated singlet oxygen and hydroxyl radicals, followed by immunogenic cell death. Wei et al. reported four NIR-based diruthenium complexes (32) and studied their anticancer activity, which is triggered by light (700 nm LED light).⁶² A series of dinuclear Ir(III) complexes were synthesized by Zeng et al. for PDT and photothermal therapy (PTT) against cisplatin-resistant cancer cells (37). In PTT, light energy is converted into heat, leading to the thermal ablation of cancer cells. Upon exposure to infrared (IR) radiation, these complexes induce reactive oxygen species (ROS)-mediated cell disruption alongside thermal ablation, enhancing their therapeutic efficacy.⁶³

A plethora of heteromultinuclear complexes has been designed with different metals containing more than one metal center. These complexes collectively acquire the advantages of the metals present in one complex. Many research groups have reported the presence of heteromultinuclear complexes with strong anticancer activity.^64,65 Notably, the first Ru–Re bimetallic tetranuclear complex 38, based on 2,2′-bipyrimidine, was successfully synthesized in Karges’ laboratory.⁶⁶ Necrosis-induced cell death has been observed by the novel mixed metallic complex when tested against multiple cancer cell lines, viz. colon, breast, pancreas, and human fibroblast cancer cell lines (Fig. 2).

Fig. 2 Few selected representative metal complexes and ligands used for complexation.

Conclusion and future perspective

Ru/Rh/Re/Ir-based anticancer complexes employ various therapeutic mechanisms, including photodynamic therapy (PDT), sonodynamic therapy (SDT), chemodynamic therapy (CDT), and photothermal therapy (PTT), to enhance their anticancer efficacy (Fig. 3). Despite extensive ongoing research on metallopharmaceuticals as anticancer agents, a huge number of unsolved hurdles are decorated in the pathway, e.g. intracellular targets, and pharmacokinetic behavior. Additionally, the toxicity of the metallodrugs cannot be ruled out. Before the application of metallodrugs, emphasis should be given to the biodistribution process. Extensive in vivo studies should be performed using different models, such as tumor xenograft models and animal species. The mechanism of drug resistance can be addressed through a multitargeted approach in the design of Ru/Rh/Re/Ir-based drugs for cancer therapy. Additional research is urgently required to address long-term safety issues and related potential adverse effects. In drug designing technique, one of the major challenges is the lack of pharmacokinetic data and in vivo toxicity, which directly affect the clinical trial phase of metallodrugs and are a primary reason for their failure in later stages of clinical application. The pharmacological features of metallodrugs should be studied in detail to clarify the mechanisms underlying their anticancer effects of the metallopharmaceuticals. Smart drug designing (synthetic) techniques in combination with tumor biology will hopefully generate novel anticancer drug molecules through interdisciplinary research among chemists, biologists, and pharmacologists to alleviate the pain of patients with cancer in a major way.

Fig. 3 Schematic of the mechanism of action of different therapeutic techniques used in metal-based anticancer complexes.

Synthetic routes should be modified to increase yield and scalability, whereas the introduction of organelle-targeted ligands could help explore the possibilities for better action. Further fine-tuning of these metal complexes is required to reach the clinical trial phase. Focus should be given to rigorous in vivo studies, with a strong emphasis on understanding pharmacokinetics, biodistribution, immunogenicity, long-term toxicity reduction, and clinical studies. Tumor-specific drug delivery can be achieved through the designing of metallopharmaceuticals increasing strong binding affinity with carriers like human serum albumin, high charge density, low toxicity, high cell permeability, and high dissociating ability within the target cell. In this regard, photodynamic therapy is proven to be the better option, where after reaching the target, the complexes show their photoactivity upon irradiation with light energy. Additionally, receptor-mediated targeting and nanoparticle-based drug delivery systems enhance the selective accumulation of the complex in cancer cells, thereby minimizing the toxicity to healthy cells. We hope that this frontier will stimulate researchers to explore and focus on developing new metallopharmaceuticals that can act as new anticancer agents.

Author contributions

S. U., R. C. and P. P. designed and wrote the manuscript.

Data availability

All the data are included in the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

The authors are grateful to the Department of Science and Technology, Government of India, for supporting the work through the DST-SERB CRG project grant (CRG/2021/002267).

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