A glimpse into the developments, potential leads and future perspectives of anticancer cobalt complexes

Abstract

The unanticipated finding of cisplatin's anticancer properties prompted extensive investigations into different platinum-containing complexes as anticancer agents. However, the side effects and resilience of cancerous cells to platinum complexes triggered investigations on non-platinum anticancer complexes. As a result, several non-platinum complexes have been developed. Among these, the anticancer potential of cobalt complexes has been recognized over the past few decades. Inorganic medicinal chemists are fascinated by cobalt complexes, as these complexes interact with cellular proteins and macromolecules, causing cellular disruption and stopping the division, growth and multiplication of cancer cells. Owing to the increasing interest of researchers in the development of anticancer cobalt complexes, this paper critically reviews the developments in the design and development of these complexes. The results of the in vitro and in vivo investigations of anticancer profiles of cobalt complexes with ligands such as Schiff bases, quinolines, carbonyl groups, polypyridyl ligands, macrocycles, thiosemicarbazones, active pharmaceuticals, natural products, etc. are reviewed. Importantly, the intervention of nanotechnological approaches in amplifying the therapeutic properties of anticancer cobalt complexes is discussed. Besides, the modes of action of anticancer cobalt complexes are highlighted. Moreover, pharmacologically significant cobalt complexes with equal or better anticancer effects than that of standard anticancer agents are identified. Finally, the existing challenges and future perspectives in research on the design and development of anticancer cobalt complexes are discussed.

In response to the increasing investigations on anticancer cobalt complexes, this paper critically reviews the advances in the design and development of these complexes.

1. Introduction

Cancer is classified as a non-communicable disease of genetic origin. It is caused by the carcinogen-triggered activation of proto-oncogenes and the deactivation of tumour suppressor genes. Cancer genesis is a multistep process involving body's multiple physiological systems, which complicates its treatment.^1,2 Primarily, cancer is confined to a specific tissue or part of the body, but over time, it spreads to other nearby and distant body sites through a process called metastasis, further complicating treatment.³ Globally, cancer is the second most common cause of human deaths.⁴ It is projected that the frequency of cancer cases worldwide will increase by 12.8% in 2025 as compared to 2020. In India, the total number of cancer cases in 2022 was 1 461 427.⁵ According to Siegel and coworkers, 2 041 910 new cases of cancer and 618 120 deaths due to cancer are estimated to occur in America by the end of 2025.⁶ Santucci et al.⁷ predicted 1 270 800 deaths due to cancers in the European Union in 2024. Cancer was ranked as the fifth most dominant cause of death in Africa in 2022.⁸ Several emerging countries in the sub-Saharan Africa are experiencing a rise in cancer-related deaths.⁹ Experts estimate that the number of new cancers will rise by 47.4% in males from 380 306 in 2015–19 to 560 744 in 2040–44 and by 54.4% in females from 313 263 in 2015–19 to 483 527 in 2040–44 in Australia.¹⁰ Globally, the most common cancers are those of the breast, lung, liver, cervix, colon, rectum, stomach, prostate and esophagus. Overall, cancer remains a major global public health issue, and its treatment and management have long been top priorities for researchers.

Presently, different treatment modalities including surgery, immunotherapy, radiotherapy, bone marrow transplantation, hormone therapy and chemotherapy are employed in the treatment and management of cancer. The utilization of a particular treatment modality is determined by the location, grade and stage of the tumour, and the general health condition of the patient.¹¹ Out of the above-listed cancer treatment approaches, chemotherapy, which involves the use of anticancer drugs (organic molecules, organometallics and coordination complexes) for treating cancer, is the most commonly used approach. The advantage of using chemotherapy is that a cytotoxic agent kills cancer cells present anywhere in the body.¹²

Metal complexes provide a great deal of promise as multifunctional platforms for practical drug design approaches. As a result, metal complexes have acquired a trailblazing position in inorganic medicinal chemistry.^13–18 The most well-known metal complex used in cancer treatment is cisplatin (Fig. 1).¹⁹ Chemotherapeutic treatment of cancer significantly improved since the unforeseen finding of cisplatin's anticancer properties.²⁰ The revelation of cisplatin's anticancer potential was followed by the rational design and development of a number of cisplatin analogues, such as oxaliplatin, carboplatin, heptaplatin, nedaplatin and lobaplatin (Fig. 1). These second- and third-generation analogues of cisplatin are all used as anticancer drugs. However, cisplatin and its analogues exhibit certain side effects such as nephrotoxicity, ototoxicity, myelosuppression, neurotoxicity, cytopenia, anaphylaxis, cardiotoxicity, hepatotoxicity, nausea, mucositis, diarrhoea, alopecia, stomatitis, pain, cachexia, anorexia, and asthenia. Besides, only few malignancies have been successfully treated with the available metallodrugs. Furthermore, the effectiveness of these drugs is reduced by resistance of cancer cells.^21–23 These observations tempted scientists to design safe and efficient anticancer metal complexes by using platinum and other metal ions/atoms. Consequently, a large pool of metal complexes have been developed and screened for their cytotoxicity in a number of cancer cell lines.²⁴ Several metal complexes containing non-platinum metal centers such as titanium, iridium, nickel, scandium, manganese, cerium, chromium, cobalt, copper, vanadium, lanthanum, molybdenum, zinc, gallium, zirconium, cadmium, nobelium, technetium, yttrium, tin, ruthenium, iron, rhodium, gold, palladium, silver, antimony, tungsten, rhenium, osmium, bismuth and neodymium (Fig. 2) have been synthesized with the promise of exciting anticancer properties.²⁵ Among the non-platinum metals, ruthenium is the most commonly employed metal ion for the development of anticancer metallodrugs, followed by copper, gold, palladium, and iron.

Fig. 1. Chemical structures of cisplatin and its second- (carboplatin, oxaliplatin and nedaplatin) and third- (heptaplatin and lobaplatin) generation analogues.

Fig. 2. Diagrammatic representation of the shift in interest in the development of anticancer metallodrugs from platinum to non-platinum complexes.

Until the last decade, cobalt complexes were scarcely investigated for their anticancer properties. The lack of researchers' interest in investigating cobalt complexes was due to their redox instability, poor selectivity, little understanding of anticancer mechanisms, undesirable interactions with biomolecules, and sequestration by important proteins. However, cobalt is a vital chemical element for sustaining life. Cobalt as cobalamin (vitamin B12) is very essential for sustaining neurological and immunological responses, formation of RBCs, DNA (deoxyribonucleic acid) synthesis, and growth and development of newborn babies.^26–30 Besides, cobalt has been reported to exhibit protecting effects towards cardiac, renal and nervous tissues.³¹ Interestingly, a large number of cobalt(ii) and cobalt(iii) complexes have been reported with interesting biological properties, including anticancer.^32–39 Failes and Hambley⁴⁰ reported several cobalt(iii) complexes of hydroxamic acids that have been reported as hypoxia-triggered anticancer prodrugs. These complexes release active ligands for exhibiting cytotoxic effects in response to decrease in the reducing environment of cancerous tissues. Moreover, cobalt complexes damage and destroy cancer cells through DNA distortion, inhibition of protein synthesis and generation of ROS (reactive oxygen species).⁴¹ The induction of apoptosis via both the extrinsic and intrinsic pathways has been documented by Alghamdi and coworkers by investigating cobalt(ii) diphenylazodioxide complexes against SK-HEP-1 (human hepatic adenocarcinoma) cells.⁴² Above all, both cobalt(ii) and cobalt(iii) complexes have shown intriguing anticancer properties, with exceptional cytotoxicity towards several cancer cells.^43–48 Noteworthily, the distinct chemical abilities and structural adaptability of cobalt complexes make them a focus of continuing research as leads for the rational design of anticancer drugs. Taking together the biocompatibility of cobalt and the results of recent investigations of anticancer properties of cobalt complexes, along with an understanding of the mechanisms behind their anticancer effects, shall enable the development of more tailored and efficient anticancer cobalt complexes at par with anticancer ruthenium complexes.

2. Need of this review

A thorough literature search was conducted using Google Scholar. More than 430 research publications have documented the anticancer potential of cobalt complexes. An examination of the figures of publications on “anticancer cobalt complexes” was carried out from 2005 to 2024. The period from 2005 to 2024 was divided into four half-decades, namely 2005–2009, 2010–2014, 2015–2019 and 2020–2024, as shown in the graph (Fig. 3). Analysis of the data shows a significant growth in the number of research publications, from 30 in 2005–2009 to 60 in 2010–2014, to 121 in 2015–2019, and finally 228 during 2020–2024. After thorough analysis of the available literature, it was found that only a few reviews have been published on anticancer cobalt complexes.^41,49,50 One of the published reviews describes the research studies conducted on anticancer cobalt-Schiff base complexes. The other review published in 2015 is quite old, which reviews the physiologically relevant redox characteristics and applications of cobalamin as a cancer cell-specific delivery vehicle for cytotoxins and the significance of cobalt complexes in the development of hypoxia specific imaging agents and prodrugs. The third review has been recently published, focusing on the anticancer properties of cobalt complexes of heterocyclic ligands. Thus, it was thought meaningful to critically review the overall recent developments in anticancer cobalt complexes. This review addresses the recent advances in anticancer cobalt complexes based on ligand systems such as Schiff bases, quinolines, carbonyl groups, polypyridyl ligands, macrocycles, thiosemicarbazones, active pharmaceuticals, natural products, etc. Importantly, the use of nanotechnology in enhancing the anticancer profiles of cobalt complexes is reviewed. Besides, the mechanism of action of anticancer cobalt complexes is discussed. Interestingly, pharmacologically significant cobalt complexes with similar or better anticancer profiles than those of the market-available anticancer drugs are identified. Finally, the prevailing challenges and future vision on the research on anticancer cobalt complexes are discussed. This paper is expected to serve as an informative and updated secondary source of literature for scientists working on the development of anticancer cobalt complexes.

Fig. 3. Graphical representation of the increasing interest in research on anticancer cobalt complexes.

3. Cobalt complexes as anticancer agents

Similar to platinum complexes, cobalt complexes exhibit a broad range of geometries, oxidation states, coordination numbers and ligand binding affinities from a chemical and physical perspective. For this reason, cobalt chemistry has been exhaustively investigated, both in general and in the quest of developing novel anticancer drugs.^51,52 Remarkably, cobalt(iii) complexes have distinct modes of action as compared to platinum-based anticancer complexes, even though they share the identical electronic configuration (d₆) with platinum(iv) prodrugs.⁵³ The interchange of axial ligands in cobalt complexes is facilitated by the reduction of inert oxidized cobalt(iii) state to labile cobalt(ii).^54–56 Irreversible activity suppression occurs when complexes bind to the residues of histidine in or close to the active sites of proteins.^57,58 As a result, Co(iii) complexes block the activity of histidine-containing enzymes and proteins such as mitochondrial endopeptidases and zinc finger transcription factors. As shown schematically (Scheme 1), protein inhibition occurs via dissociative exchange of labile ligands (axial) with the imidazole nitrogen atom of histidine residues.^59,60 Interestingly, cobalt is not as harmful to humans as platinum, which supports research into cobalt-containing complexes as less toxic substitutes for anticancer metallodrugs based on platinum^61,62 Although, Co(iii) ion is not stable in aqueous media, it could be stabilized by chelating with ligands containing N, O, or N, S donors, which prevents its reduction to Co(ii).⁴¹ Importantly, cobalt(iii) complexes prepared from such ligands have displayed exciting anticancer properties.⁶³

Scheme 1. Schematic of the binding of cobalt to the residues of histidine via dissociative exchange of axial ligands, as reported by Haffern et al.⁵⁹.

Cobalt occurs in many distinct oxidation states (0, +1, +2, +3 and +4) in inorganic complexes. However, cobalt(ii) and cobalt(iii) complexes are the widely reported cobalt complexes displaying anticancer properties. Cobalt ions cause hypoxia in cells, which activates a number of signalling pathways including hypoxia-inducible transcription factors.^31,64 Three different inorganic cobalt salts, namely, cobaltous (CoCl₂·6H₂O), macro-Co(ii,iii) oxide and nano-Co(ii,iii) were approved for the inhibition of proliferation of the PC-3 (human prostate cancer cell line) cancer cell line. Amongst the tested cobalt salts, CoCl₂·6H₂O was reported as the most potent antiproliferative agent.⁶⁵ Cobalt complexes kill cancerous cells by causing DNA distortion and protein inhibition, and through the generation of ROS.⁴¹ Interestingly, cobalt complexes have displayed activity against both cancer and cancer stem cells.⁶⁶ The literature witnesses cobalt(iii) bearing different types of ligands such as polypyridyl ligands, tetraaza macrocyclic ligands, thiosemicarbazones, peptide ligands, and Schiff bases, as DNA intercalators and anticancer agents.^67–70 Overall, cobalt complexes with various ligand systems have demonstrated intriguing anticancer profiles towards several human cancer cell lines. The anticancer activity mechanisms of cobalt complexes differ from those of platinum complexes, which is by far their most significant feature. Another benefit is that the anticancer effects of some cobalt complexes' rely on their redox behaviour. In addition, there is a great deal of thought given to the possibility that some anticancer cobalt complexes might overcome the resilience of cancer cells towards anticancer drugs.

4. Developments in anticancer cobalt complexes

Research on developing metallodrugs with anticancer properties is quite popular. Due to the biological importance of cobalt owing to its involvement in several critical biochemical processes, cobalt complexes are currently the subject of intense research as potential anticancer drugs. Promising results have been obtained in the recent developments pertaining to anticancer cobalt complexes.^71–74 Through a variety of modes, such as DNA binding, reduction of cell growth, and activation of apoptosis, cobalt complexes demonstrate cytotoxic effects on cancer cells. In order to increase the anticancer efficacy of these complexes and lessen their systemic toxicity, attention is now being paid to the development of structurally tuneable complexes and their tailored delivery methods. All facts considered; the recent developments demonstrate the promise of cobalt complexes as novel anticancer agents. The developments in the rational design and development of cobalt complexes with different ligand systems as anticancer agents are reviewed in the succeeding sub-sections.

4.1. Cobalt complexes bearing Schiff bases as ligands

Schiff bases are widely used as ligands with diverse bioactivities owing to their facile synthesis and interesting solubility properties.⁷⁵ Schiff bases metalate with transition metals to form stable coordination complexes. Schiff bases with donor atoms such as N and O are crucial for the successful occurrence of important processes in natural biological systems, particularly due to their azomethine groups.⁷⁶ Schiff bases exhibit several biological effects including anticancer, antibacterial, anti-oxidant, antidiabetic and antifungal activities.⁷⁷ Metal complexes with Schiff bases bearing azomethine moieties exhibit biological and pharmacological features, making them useful in drug design rationales, analytical chemistry, catalysis and material design. Schiff bases bearing azomethine groups also serve as model compounds for the metalloprotein structure and function.^78–82 There are two important reasons for the utilization of Schiff bases as preferred ligands for designing and developing metal complexes with anticancer properties.⁸³ One is that the majority of Schiff bases exhibit inherent unique biological properties including anti-inflammatory and anticancer effects,^84,85 and they essentially synergize with metal ions.⁸⁶ The other is that, under typical conditions, the specifically engineered multidentate Schiff base ligands may readily chelate metal ions to form stable targeted complexes.⁸⁷ In view of the importance of Schiff bases for developing therapeutic metal complexes, Zhao et al.⁸⁸ demonstrated the anticancer activities of cobalt(ii) complexes (Fig. 4: complexes 1–4) against human cancer cell lines, namely MGC-803 (human gastric carcinoma cell line), HepG2 (human hepatocellular carcinoma), HeLa (human cervical carcinoma cell line), T24 (human urinary bladder cancer cell line), A-549 (human non-small cell lung carcinoma), and SK-OV-3 (human ovarian cancer cell line), and normal cell lines, namely Wi-38 (human fetal lung fibroblasts) and HL-7702 (human hepatic cell line). The complexes were active towards the screened cancer cell lines. Interestingly, complexes 1–4 displayed better activity in comparison to cisplatin. However, complexes 1, 2 and 4 were more toxic to normal cell lines. However, complex 3 with an IC₅₀ (half maximum inhibitory concentration) value of 21.93 ± 1.87 μM was more selective towards normal cells, HL-7702, than cisplatin (IC₅₀ = 20.51 ± 1.45 μM). Complex 3 activated caspase 3/9, lowered mitochondrial membrane potential, enhanced ROS, and arrested cell cycle in the G1 (growth 1) phase, which triggered cell death via the mitochondrial route.

Fig. 4. Chemical structures of trinuclear cobalt(ii) complexes bearing Schiff base ligands, as reported by Zhao et al.⁸⁸.

Multinuclear complexes contain two or more than two metal centers within a single complex. Multinuclear complexes have been known to display enhanced interactions with biological targets including proteins, DNA, and enzymes, due to the presence of more than one active metal center. Thus, multinuclear complexes are increasingly being preferred in anticancer drug development rationales.⁸⁹ In line with these facts, Ahamad and coworkers⁹⁰ documented the anticancer activities of dinuclear cobalt(ii) complex containing a Schiff base ligand (Fig. 5: complex 5) against HeLa and A-549 cell lines. The complex displayed activity towards A-549 and HeLa cells with IC₅₀ values in the range of 7 to 30 μM (micromolar concentration). The complex exhibited stronger anticancer effects than cisplatin (IC₅₀ = 10.5 to 40 μM). Cancer cells tested with the complexes were examined for the apoptosis mechanisms, and it was revealed that the cells had a decreased morphology in addition to nuclear alterations, which indicated apoptosis. The overall results indicated the promising potential of this complex as an anticancer drug.

Fig. 5. Chemical structure of the dinuclear cobalt(ii) complex, as reported by Ahamad and coworkers.⁹⁰.

In an interesting study, Gowdhami et al.⁹¹ documented the cytotoxicity and toxicity of two cobalt(iii) Schiff base complexes (Fig. 6: complexes 6 and 7) towards MCF-7 (human breast carcinoma cell line) and A-549 cancer cells and normal 3T3 cells, respectively. The complexes have been previously synthesized by Ambika and coworkers.⁹² Complexes 6 and 7 showed cytotoxic effects towards MCF-7 cells at low concentrations of 08.56 ± 0.07 and 03.55 ± 0.88 μM. Complex 7 was more effective than complex 6 towards MCF-7 cells. Interestingly, in normal 3T3 cells, both complexes were cytotoxic at extremely high concentrations. The two complexes were reported to induce apoptosis in MCF-7 cells by the modulation of gene expressions of pro-apoptotic, anti-apoptotic, and ROS modulatory pathways. Overall, the two cobalt(iii) Schiff base complexes destroyed MCF-7 cells at considerably lower doses than those of 3T3 cells. Overall, this research report revealed that cobalt(iii) Schiff base complex 7 should be investigated further in vivo against different cell lines.

Fig. 6. Chemical structures of the cobalt(iii) Schiff base complexes (6 and 7) reported by Ambika et al.⁹² and investigated for their anticancer profiles by Gowdhami et al.⁹¹.

Doxovir is a Co(iii) Schiff base complex bearing a bis(acetylacetone)ethylenediamine ligand and two 2-methylimidazole rings.⁹³ Doxovir is under clinical trials for the treatment of drug-resistant herpes simplex virus.⁹⁴ This complex inspired Liao et al.⁹⁵ for investigating the cytotoxic activity of the Schiff base cobalt(iii) complex 8 (Fig. 7) against A-549, LoVo (colon carcinoma cell line), HeLa and A-549/CDDP cancer cell lines, and the normal cell line, LO2 (human fetal hepatocyte cell line). Complex 8 efficiently caused inhibition of all the screened cancer cells. The IC₅₀ value of complex 8 towards HeLa cells was 12.40 ± 2.78 μM, comparable to cisplatin (9.74 ± 0.31 μM). Against the cisplatin-resistant A-549/CDDP cells, complex 8 successfully overcame drug resistance. The IC₅₀ value of complex 8 against A-549/CDDP cells was 18.03 ± 2.66 μM, roughly 2.50-fold lower than that of cisplatin (44.79 ± 2.75 μM). In LO2 cells, the IC₅₀ value of complex 8 (6.27 ± 0.27 μM) was higher than that of cisplatin (2.61 ± 0.89 μM). Additionally, complex 8 had a higher SI (selectivity index) than that of cisplatin, potentially reducing the severe side effects associated with cisplatin.

Fig. 7. Chemical structure of the cobalt(iii) complex containing a Schiff base ligand, as reported by Liao et al.⁹⁵.

Chromones have been demonstrated to display fascinating cytotoxic, anti-inflammatory, antimicrobial, anti-HIV, and anticonvulsant properties. Besides, chromones are effective in inhibiting tyrosinase and some viral enzymes, and destructing some bacterial strains and certain pathogenic protozoans.^96–98 Schiff bases obtained from chromone-3-carbaldehyde and thiosemicarbazides have been reported to possess interesting bioactivities. In addition, the bioactivities of such Schiff bases have been found to increase upon complex formation with a number of transition metal ions.^99–102 In light of these facts, Kalaiarasi et al.¹⁰³ studied the anticancer effects of cobalt(iii) complexes bearing 7-hydroxy-4-oxo-4H chromene Schiff bases (Fig. 8: 9–12) against MCF-7 and A-549 cancer cells, and healthy cells, HaCaT (human keratocytes). Importantly, complex 11 displayed the strongest activity. The cytotoxic activity of the complexes towards MCF-7 and A-549 cells followed the order of 11 (MCF-7, IC₅₀ = 4.62 ± 0.05 μM and A-549, IC₅₀ = 5.41 ± 0.04 μM) > 10 (MCF-7, IC₅₀ = 5.04 ± 0.03 μM and A-549, IC₅₀ = 5.7 ± 0.05 μM) > 9 (MCF-7, IC₅₀ = 5.4 ± 0.06 μM and A-549, IC₅₀ = 5.83 ± 0.04 μM) > 12 (MCF-7, IC₅₀ = 5.6 ± 0.04 μM and A-549, IC₅₀ = 6.54 ± 0.07 μM). Interestingly, all the complexes displayed higher activities than cisplatin.

Fig. 8. Chemical structures of the cobalt(iii) complexes (9–12) documented by Kalaiarasi et al.¹⁰³.

Overall, cobalt complexes with Schiff base ligands of various chemical architectures have shown encouraging anticancer properties. Several complexes have displayed better therapeutic profiles than cisplatin. However, more work needs to be done to investigate novel ligands and ligand systems whose complexation with cobalt can lead to complexes with better anticancer profiles.

4.2. Cobalt complexes with quinoline-derived ligands

Metal complexes of quinoline-derived ligands have fascinated researchers owing to their remarkable uses in material science, catalysis and medicinal chemistry. These complexes exhibit exceptional physicochemical, electronic, coordinating and steric properties, which make them suitable candidates for several useful applications.¹⁰⁴ Several complexes of transition metals with 8-hydroxyquinoline have displayed potential as remarkable inhibitors of DNA^105–107 and proteins.^108,109 Besides, such complexes have displayed potential as amyloid-β oligomer drugs,^110,111 photosensitizers^112,113 and antineoplastic agents.^114–119 Additionally, these complexes are proven inhibitors of basic fibroblast growth factor-mediated angiogenesis,¹²⁰ topoisomerase IIa¹²¹ and other telomerases,¹²² and have also been reported as inductors of cell autophagy.^123,124 Several 8-hydroxyquinoline derivatives and their cobalt(iii) complexes have exhibited exciting anticancer activities.^125–128 Despite the fact that several active complexes of cobalt(ii) containing 8-methoxyquinoline have been identified,^129,130 their mechanisms of apoptosis are still unclear. Zhang et al.¹³¹ investigated the DNA binding and anticancer activity of cobalt(ii) complexes of 5-chloro-8-hydroxyquinoline (Fig. 9: complex 13) against SK-OV-3, BEL-7404 (cellosaurus cell line), HeLa229, T24, and MGC-803 cancer cell lines, and HL-7702, a normal cell line. The complex demonstrated profound activity towards all the examined cancer cell lines. It showed the maximum activity towards T24 cells with an IC₅₀ value of 7.04 ± 0.06 μM. Besides, the complex was more potent than cisplatin (IC₅₀ = 14.05 ± 0.03 μM) towards T24 cells. Moreover, the complex displayed better selectivity and less toxicity against HL-7702 cells (IC₅₀ = 30.08 ± 0.04 μM) in comparison to cisplatin (IC₅₀ = 5.04 ± 0.06 μM). Triggered by the results, in another investigation, Zhang et al.¹³² documented the anticancer properties of cobalt(ii) complexes of 8-hydroxyquinoline derivatives (Fig. 10: complexes 14–16) towards T24, HepG2, MGC-803, BEL-7404, HL-7702, HeLa, SKOV-3 and WI-38 cancer cell lines. The complexes displayed strong activity towards T24 cells (IC₅₀ = 7.00–16.70 μM). However, the complexes displayed lower cytotoxicity towards HL-7702 and WI-38 cell lines in comparison to T24 cells. Complex 14 showed the maximum cytotoxicity against T24 tumour cells (IC₅₀ = 7.00 ± 0.06 μM). Complex 14 was taken as a typical complex in mechanistic experiments with T24 cells. The complex induced apoptotic death in T24 cells by causing the arrest of the G1 phase of cell cycle. Besides, it caused the overproduction of ROS, resulting in mitochondria-mediated apoptosis.

Fig. 9. Chemical structure of the cobalt(ii) complex of 5-chloro-8-hydroxyquinoline (13) documented by Zhang et al.¹³¹.

Fig. 10. Chemical structures of the cobalt(ii) complexes of 8-hydroxyquinoline derivatives (14–16), as reported by Zhang et al.¹³².

The development of metal complexes with high cytotoxicity towards cancer cells and little or no toxicity towards normal cells is always the primary goal of any drug development regimen. More importantly, the preliminary investigations are focused on the development of complexes displaying efficient in vitro and in vivo therapeutic profiles. In an attempt to develop cobalt complexes with high in vitro and in vivo anticancer activities, Meng et al.¹²⁶ reported several bis-chelate cobalt(ii) complexes of 5,7-dihalo-8-quinolinol–phenanthroline derivatives. All the complexes demonstrated anticancer efficacy against HeLa cancer cells in vitro displaying low IC₅₀ values (0.8–11.88 μM). In addition, the complexes exhibited in vivo activity towards HeLa xenograft tumour formation with TIR (toll/interleukin-1/receptor protein) = 43.7%, p < 0.05). Out of the screened complexes, complex 17 (Fig. 11) exhibited the maximum cytotoxic activity with IC₅₀ value of 0.80 ± 0.21 nM (nanomolar concentration) that was around 18 folds higher than that of cisplatin (IC₅₀ = 15.03 ± 1.05 μM). Besides, the complex showed little toxicity towards normal HL-7702 cells. In in vivo investigations, complex 17 demonstrated anticancer efficacy in HeLa xenograft development (TIR = 43.7%, p < 0.05) (Fig. 12). The complex 17 reduced telomerase activity and induced G2/M phase arrest. Besides, the complex triggered mitochondrial dysfunction at very low concentrations. The overall analysis with respect to the higher cytotoxicity and selectivity of complex 17 in comparison to cisplatin suggested that the complex might work as a promising lead complex for the discovery of potent cobalt-based anticancer agents.

Fig. 11. Chemical structure of the bis-chelate cobalt(ii) 5,7-dihalo-8-quinolinol–phenanthroline (complex 17), as reported by Meng et al.¹²⁶.

Fig. 12. In vivo anticancer activity of the complex 17 at 2.0 mg per kg body weight for 21 days in a HeLa xenograft. Reprinted with permission from ref. 126. Copyright 2019 American Chemical Society.

A number of metal complexes containing 8-hydroxyquinoline-based ligands have been found to function as DNA intercalators,¹⁰⁵ amyloid-β oligomer drugs,¹¹⁰ protein synthesis inhibitors,¹⁰⁸ mitochondrial apoptosis-related anticancer agents,¹¹⁴ topoisomerase IIa inhibitors,¹²¹ and telomerase inhibitors.¹³³ Previously, several cobalt(iii) complexes of 8-hydroxyquinoline-based ligands have shown remarkable anticancer activities.¹²⁵ Keeping these facts in consideration, Wang et al.¹³⁴ documented the anticancer properties of three cobalt(ii) complexes containing quinoline derivatized ligands (Fig. 13: 18–20) towards SK-OV-3/DDP (cisplatin-resistive human ovarian cancer cell line), SK-OV-3 and HL-7702 cancer cell lines. The complexes displayed a better anticancer activity than that of cisplatin. The cytotoxicity of complex 18 (which had the lowest IC₅₀ values) was higher than that of complexes 19 and 20. Moreover, complex 18 exhibited much greater cytotoxicity towards SK-OV-3/DDP cells than the earlier documented metal complexes of 8-hydroxyquinoline derivatives.^{106,108,110,112,116,121,124,127,133,135,136} The anticancer activity of complexes 18, 19 and 20 against SK-OV-3/DDP tumour cells was higher by 156, 69, and 46 folds, respectively, in comparison to HL-7702 cells. Moreover, in the SK-OV-3 tumour xenograft, complex 18 demonstrated better anticancer activity in vivo (about 60.1%) in comparison to complex 20 (about 48.8%) (Fig. 14). Overall, the cobalt(ii) complexes based on 8-methoxyquinoline showed promise as effective anticancer agents.

Fig. 13. Chemical structures of cobalt(ii) complexes of quinoline derivatives (18–20), as reported by Wang et al.¹³⁴.

Fig. 14. In vivo anticancer activities of complexes 18 and 20 at 15 mg per kg body weight for 2 days in mice (BALB/c nude mice) using an SK-OV-3 xenograft model. Reprinted with permission from ref. 134. Copyright 2022 Royal Society of Chemistry.

The arguments made in this sub-section reveal that a number of cobalt complexes of quinoline-based ligands have demonstrated intriguing anticancer activities towards different human cancer cell lines. Besides, several cobalt complexes of quinoline-based ligands have demonstrated selectivity to cancer cells without affecting healthy cells, along with unique modes of action. In view of these findings, more research is encouraged in order to obtain quinoline-derived cobalt complexes with better therapeutic profiles in terms of activity and selectivity in vivo. This may be a better part towards the development of safer and more active anticancer drugs.

4.3. Cobalt complexes containing carbonyl groups

Carbonyl groups are inorganic moieties and may therefore be classified as inorganic ligands. Dicobalt hexacarbonyl [Co₂(CO)₆] complexes have been recognized as important leads in medicinal chemistry.⁴¹ The moieties associated with the [Co₂(CO)₆] core determine the target specificity of [Co₂(CO)₆] complexes to cells and tissues. Jung and coworkers¹³⁷ studied the anticancer profiles of cobalt(ii) complexes containing carbonyl groups as ligands (Fig. 15: complexes 21–23) against 3677 and H2981 (lung adenocarcinoma cell line). The results obtained were compared with the results of untreated cells or the reference, phenylenediamine mustard, which has been shown to have a substantial cytotoxic impact.¹³⁸ As previously reported by Kerr et al.,¹³⁸ 3677 melanoma cells are sensitive to phenylenediamine mustard (IC₅₀ = 1 μM). Complexes 21, 22 and 23 showed significant cytotoxicity towards 3677 cells. The IC₅₀ values of the complexes ranged from 10 to 20 μM, indicating 10-fold enhancement of activity over Co₂(CO)₆. Similar findings were achieved using the H2981 cell line. These results indicated that cobalt-acetylene complexes display cytotoxic effects towards tumour cells. Besides, the results obtained on the H2981 cell line showed that the attached ligand can affect the cytotoxic activity. Based on these findings, it must be worthwhile to investigate a diverse set of ligands with ability to interact with cell growth or death, so that a better understanding of the anticancer potential of cobalt-acetylene complexes is achieved.

Fig. 15. Chemical structures of the cobalt(ii) complexes containing carbonyl groups as ligands (21–23), as reported by Jung and coworkers.¹³⁷.

Glycyrrhizin is a natural substance with several beneficial pharmaceutical properties. It is a commonly used anti-hepatitis B medication in clinical settings worldwide. GA (glycyrrhetinic acid) is a biologically active metabolite of glycyrrhizin, which is a key active constituent in anti-hepatitis B treatments.¹³⁹ GA has been reported to reverse multidrug resistance to antitumour drugs.¹⁴⁰ Owing to the pharmacological significance of GA, Li et al.¹⁴¹ investigated the cytotoxicity of several cobalt(ii) carbonyl complexes containing GA (Fig. 16: 24–28) towards HeLa, A-549, HT29 (human colorectal adenocarcinoma), SMMC7721 (human hepatocarcinoma cell line) and HepG2 cancer cell lines. The complexes demonstrated effective anticancer activities towards HepG2 and SMMC7721 cancer cell lines. The complexes 24–27 displayed profound cytotoxicity with IC₅₀ values ranging from 10.07 to 66.06 μM. Thus, the complexes were equally or even more active than cisplatin (IC₅₀ range from 29.37 ± 0.26 to 40.16 ± 0.19 μM) towards the investigated cell lines. Interestingly, the complexes exhibited stronger cytotoxicity against HepG2 and SMMC7721 cells compared to other cell lines. The complexes increased caspase-3 and Bax expression levels while decreasing Bcl-2 expression in HepG2 cells leading to dose-dependent apoptosis. In conclusion, these complexes show promise as anticancer agents and need further in vivo investigations.

Fig. 16. Chemical structures of the cobalt(ii) carbonyl complexes containing GA (24–28), as reported by Li et al.¹⁴¹.

Rational modifications in nucleoside bases have led to the development of significant therapeutic analogues and leads.^142–144 Nucleoside derivatives and analogues have been employed for treating cancers including both haematological malignancies and solid tumours. Nucleoside analogues act as antimetabolites. They are known to compete with important physiological nucleosides, and therefore, undergo interaction with several essential intracellular targets for inducing cytotoxicity.^145,146 Ethynyl (acetylenic) fragments have been used for modifying nucleoside bases, leading to the development of several 5-alkynyl uridines with important applications.^147–149 Considering the anticancer properties of 5-alkynyl-2-deoxyuridines¹⁴⁷ and the remarkable cytotoxicity of hexacarbonyl dicobalt moieties,^137,150,151 synergistic combination of the two seems to deliver new therapeutic compounds. In the light of these facts, Sergeant and coworkers¹⁵² reported the cytotoxic activity of hexacarbonyl dicobalt(ii) nucleoside complexes (Fig. 17: complexes 29–36) towards MCF-7 and MDA-MB-231 (human breast carcinoma cell line) cell lines. Substantial antiproliferative properties were shown by the complexes with IC₅₀ values ranging from 6.7 to 47.3 μM. The potency of the complexes was at par with the potency of drugs such as 5-fluorouracil and cisplatin. MCF-7 cells were more responsive to the effects of the complexes. Overall, the research report indicated the alkyne cobalt carbonyl organometallic fragment as a valuable moiety in medicinal chemistry investigations pertaining to the modification of the characteristics of recognized drug molecules or bioactive substances.

Fig. 17. Chemical structures of the dicobalt(ii) nucleoside complexes (29–36), as reported by Sergeant and coworkers.¹⁵².

A critical analysis of the research studies discussed in this sub-section shows that cobalt complexes containing carbonyl groups as ligands have displayed interesting anticancer characteristics. Several complexes have demonstrated anticancer activities comparable to and even better than anticancer drugs such as cisplatin and 5-fluorouracil. The research studies discussed herein warrant further investigations including in vivo studies for the rational design of effective anticancer cobalt complexes containing carbonyl groups.

4.4. Cobalt complexes with polypyridyl ligands

Metal complexes containing polypyridyl ligands exhibit optical characteristics for which such complexes find uses in many biological and technological applications. The structural diversity and chemical-redox characteristics of polypyridyl metal complexes offer a great chance to develop novel and effective anticancer leads.¹⁵³ Ravi et al.¹⁵⁴ investigated the anticancer properties of three Co(iii) polypyridyl complexes (Fig. 18: complexes 37–39) against the SK-OV-3 cell line. The MTT investigation revealed dose-dependent growth suppression and cell death. The IC₅₀ value for complex 37 was 10.4 ± 1.6 μM for 48 hours of incubation, whereas the complexes 38 and 39 had values of 14.4 ± 0.4 and 19.9 ± 1.7 μM, respectively. Cell cycle analysis from the date of flow cytometry revealed increased Sub G1 population. Interestingly, the complexes were reported to induce apoptotic cell death, which was proved from the results of annexin V FITC/PI staining studies.

Fig. 18. Chemical strictures of the cobalt(iii) polypyridyl complexes (37–39), as reported by Ravi et al.¹⁵⁴.

Pyrazole scaffolds have been employed in designing and developing selective and effective anticancer leads and drugs. During the past decade, a large number of pyrazole derivatives with interesting anticancer properties against several cancer cell lines have been documented. Exciting anticancer properties have been exhibited by pyrazole derivatives through the involvement of multiple action mechanisms.¹⁵⁵ Owing to these facts, Eskandari et al.¹⁵⁶ examined the cytotoxicity of mononuclear and dinuclear cobalt(ii) complexes bearing polypyridyl ligands containing pyrazole moieties (Fig. 19: complexes 40–42) against U2OS (homo sapiens bone osteosarcoma cells) and HepG2 cell lines, and GMO5757 (normal human fibroblast cell line) cells. The cobalt(ii) complexes exhibited micromolar cytotoxicity. All the complexes (IC₅₀ values ranging from 32.5 ± 0.6 to 61.0 ± 8.8 μM for U2OS and 38.4 ± 0.8 to 81.3 ± 5.3 μM for HepG2 cells) displayed lower activities than cisplatin (13.9 ± 0.5 μM for U2OS and 6.2 ± 0.1 μM HepG2 cells), but were more effective than carboplatin (174.5 ± 8.7 μM) towards U2OS cells. The dinuclear complexes 41 and 42 were found to have higher cytotoxic activities than the mononuclear complex 40. Complex 42 had a 2-fold lower IC₅₀ value against U2OS cells than against GMO5757 cells. Cellular mode of action analysis indicated that complex 41 (the most active complex) entered U2OS cells, reached the nucleus, triggered genomic DNA damage, and caused caspase-dependent death in a p53-independent way. This work demonstrated the effectiveness of dinuclear cobalt(ii) complexes as effective oxidative metallonucleases and powerful cytotoxic agents.

Fig. 19. Chemical structures of the mono- and di-nuclear cobalt(ii) complexes (40–42) containing polypyridyl ligands with pyrazole moieties, as reported by Eskandari et al.¹⁵⁶.

Cobalt complexes containing polypyridyl ligands exhibit interesting coordination modes, several redox behaviors, feasible kinetic pathways of substitution, and important photophysical and electrochemical properties, which ease their non-covalent interactions with DNA. Metal complexes bearing polypyridyl ligands are known to exhibit DNA binding via metal centers as well as ligands.^157,158 This prompted Karumban and coworkers¹⁵⁹ to report the anticancer activity of four mononuclear cobalt(ii) complexes containing polypyridyl ligands (Fig. 20: complexes 43–46) against MDA-MB-231 and A-549 cell lines. Complexes 43–46 significantly reduced the growth of A-549 cells, displaying IC₅₀ values of 26.48 ± 1.45 μM, 10.89 ± 0.55 μM, 7.63 ± 0.4 μM, and 37.67 ± 2.06 μM, respectively. Besides, the complexes were highly cytotoxic towards MDA-MB-231 cells, displaying IC₅₀ values of 14.45 ± 0.73 μM, 1.97 ± 0.1 μM, 0.98 ± 0.05 μM, and 24.43 ± 1.22 μM, respectively. Complexes 43–45 were more effective in causing cell death in cancer cells than complex 46. The complexes 44 and 45 outperformed complex 43 in terms of cytotoxicity. More importantly, complexes 44 and 45 outperformed cisplatin (IC₅₀ values of 20 μM and 7.5 μM against A-549 and MDA-MB-231 cells, respectively).

Fig. 20. Chemical structures of the mononuclear cobalt(ii) complexes bearing polypyridyl ligands (43–46), as reported by Karumban and coworkers.¹⁵⁹.

A keen assessment of the literature discussed above brings forth that a number of cobalt complexes bearing polypyridyl ligands have demonstrated excellent anticancer activities against different cancer cell lines. Besides, several complexes have exhibited selectivity to normal cells. A number of reported complexes have displayed higher activity than the market-available anticancer metallodrugs such as carboplatin and cisplatin. It is also evident that dinuclear complexes are better than mononuclear ones in terms of activity. Thus, the development of cobalt complexes containing polypyridyl ligands seems quite a promising approach for the rational design of effective anticancer drugs in comparison to the market-available anticancer metallodrugs.

4.5. Cobalt complexes with macrocyclic ligands

Medicinal chemists have always showed huge interest in the design, development and investigation of macrocyclic complexes with biological properties.¹⁶⁰ Several researchers have documented important biological properties including anticancer activities of macrocyclic complexes.^161–166 There are several research reports on the in vitro anticancer efficacy of macrocyclic complexes towards Hep3B (human liver cancer cell line) and MCF-7 cancer cells.^167–169 In view of the overall therapeutic importance of macrocyclic complexes, Kareem et al.¹⁷⁰ reported the cytotoxic activity of dichloro/dinitrato octaazamacrocyclic cobalt(ii) complexes (Fig. 21: complexes 47 and 48) against Hep3B, HeLa, MCF-7 and PBMC (peripheral blood mononuclear cells) cells. The cobalt complex 47 displayed good cytotoxicity against Hep3B (IC₅₀ = 3.90 ± 0.700 μM), HeLa (7.36 ± 2.060 μM) and MCF-7 (5.12 ± 2.540 μM) cancer cells. Complex 48 was more potent against HeLa cells with an IC₅₀ value of 3.95 ± 0.162 μM. Both the complexes were found to be less toxic (IC₅₀ value ranging from 12.40 ± 0.900 μM to 14.08 ± 1.500 μM) to PBMC than doxorubicin (DOX) (IC₅₀ = 8.87 ± 1.800 μM) and 5-fluorouracil (IC₅₀ = 9.91 ± 2.900 μM). Overall, this research report shows promising therapeutic potencies of the complexes, and thus, warrants further in vivo investigations of the complexes.

Fig. 21. Chemical structures of the dichloro/dinitrato octaazamacrocyclic cobalt(ii) complexes (47 and 48), as reported by Kareem et al.¹⁷⁰.

Macrocyclic complexes of d- and f-block metals containing Schiff base ligands have been examined widely for their intriguing applications.^171–178 Such complexes have shown interesting in vitro anticancer properties towards human breast and hepatocarcinoma cancer cells.^167–169 In view of these facts, Fahmi and coworkers¹⁶¹ documented the anticancer activities of several macrocyclic cobalt(ii) complexes against HeLa cell lines. Amongst the tested complexes, complex 49 (Fig. 22) displayed maximum cytotoxicity towards HeLa cell lines (IC₅₀ = 19.85 μg mL⁻¹). It was observed that upon increasing the dosage of the complexes, the HeLa cell line's percentage growth inhibition also increased. The overall results obtained from the biological investigations indicated that these complexes can serve as potential leads for designing and developing new metallo-anticancer drugs.

Fig. 22. Chemical structure of the cobalt(ii) complex containing a macrocyclic ligand (49), as reported by Fahmi and coworkers.¹⁶¹.

Tetraaza macrocyclic ligands efficiently chelate with transition metals, and their complexes have been investigated for therapeutic effects against a broad spectrum of bacteria, fungi, and some cancers.^179,180 In the light of these facts, Subhash et al.¹⁸¹ demonstrated the cytotoxicity of cobalt(ii) macrocyclic complexes (Fig. 23: complexes 50–52) towards MCF-7 and HepG2 cancer cells. The complexes demonstrated profound in vitro cytotoxicity against the investigated cancer cell lines without significantly harming normal cells. Complex 51 exhibited the strongest in vitro cytotoxicity towards MCF-7 (IC₅₀ = 18.42 ± 0.25 μM) and HepG2 (IC₅₀ = 17.94 ± 0.45 μM) cells.

Fig. 23. Chemical structures of the cobalt(ii) macrocyclic complexes (50–52), as reported by Subhash et al.¹⁸¹.

In another interesting investigation, Subhash et al.¹⁸² documented the cytotoxicity of three cobalt(ii) complexes containing tetraaza macrocyclic ligands (Fig. 24: complexes 53–55) towards MCF-7, HeLa, A-549 and IMR-32 (neuroblast cells) cell lines. All the complexes demonstrated moderate cytotoxicity against each cell line. The complexes 54 and 55 displayed the best cytotoxicity against all cancer cell types. These complexes demonstrated IC₅₀ values of 11.21 ± 0.14 μM and 10.42 ± 0.34 μM towards MCF-7 cells, 11.72 ± 0.24 μM and 11.05 ± 0.18 μM towards IMR-32 cells, 11.92 ± 0.35 μM and 11.15 ± 0.11 μM towards A-549 cells, and 15.67 ± 0.42 μM and 11.13 ± 0.15 μM towards HeLa cells. The complex 53 had a minor cytotoxic effect, with IC₅₀ values of 16.31 ± 0.23 μM and 14.63 ± 0.22 μM towards HeLa and A-549 cells, respectively. In another important investigation, Subhash and coworkers¹⁸³ investigated the cytotoxicity of cobalt(ii) macrocyclic complexes containing a N₄O₄ macrocyclic core (Fig. 25: complexes 56–58) towards MCF-7, HeLa, and A-549 cancer cell lines. The complexes displayed substantial cytotoxicity towards MCF-7 cells, while minimally damaging normal cells. Interestingly, the colorimetric viability studies indicated that the ligands and their complexes exhibited in vitro cytotoxicity at par with that of cisplatin.

Fig. 24. Chemical structures of the cobalt(ii) macrocyclic complexes (53–55), as reported by Subhash et al.¹⁸².

Fig. 25. Chemical structures of the cobalt(ii) complexes with macrocyclic ligands containing an N₄O₄ macrocyclic core (56–58), as reported by Subhash and coworkers.¹⁸³.

An assessment of the research studies discussed in the above sub-section shows that some cobalt complexes bearing macrocyclic ligands with macrocyclic cores of different compositions have demonstrated intriguing cytotoxicity towards various human cancer cell lines. Moreover, several macrocyclic cobalt complexes have selectively targeted cancer cells while being non-toxic to normal cells. Even several complexes have shown anticancer efficacy similar to that of cisplatin. Thus, future research towards the development of macrocyclic leads containing cobalt is warranted.

4.6. Cobalt complexes with thiosemicarbazones

The chemical and biological characteristics of metal complexes containing thiosemicarbazone-based ligands have garnered significant scientific interest. Several medicinal properties of thiosemicarbazones have been evaluated, including antiviral,^184,185 anticancer,^186–188 antibacterial,^189,190 anti-inflammatory and anti-amoebic activities.^191–193 Moreover, thiosemicarbazones can coordinate to different metal ions and form complexes with exciting biological properties. Considering the significance of thiosemicarbazones in the rational design and development of bioactive metal complexes, Fan et al.¹⁹⁴ demonstrated the in vitro anticancer activity of two cobalt(ii) complexes containing substituted thiosemicarbazone ligands (Fig. 26: complexes 59 and 60) towards A-549, A-549/CDDP (cisplatin-resistant human non-small cell lung carcinoma) and MCF-7 cancer cells. The complexes displayed higher activity than cisplatin towards A-549/CDDP and MCF-7 cells. Specifically, complex 60 was found to be much more cytotoxic than cisplatin towards A-549/CDDP but less active towards A-549 cells. Complex 60 had a three-fold higher inhibitory rate (53.6%) in comparison to cisplatin (18.7%) towards A-549/CDDP cells at 2 μM dosage. Interestingly, at a dosage of 20 μM, complex 60 showed an inhibition rate of 80.8%, whereas the cisplatin-triggered inhibition rate was only 36.5%. This suggested that complex 60 has the potential for evolving into an effective anticancer drug that may overcome cisplatin resistance.

Fig. 26. Chemical structures of the cobalt(ii) complexes with thiosemicarbazone-derived ligands (59 and 60), as reported by Fan et al.¹⁹⁴.

During the past few decades, metal complexes of aromatic Schiff bases with pyridoxal substitutions have fascinated researchers owing to their exciting anticancer properties.^195,196 Manikandan and coworkers¹⁹⁷ documented the anticancer activity of cobalt(iii) complexes bearing pyridoxal N(4)-substituted thiosemicarbazone ligands (Fig. 27: complexes 61 and 62) against HeLa and MCF-7 cells. The authors reported that the viability of cancer cells depended on drug concentrations (1–100 μM), with higher doses of complexes, leading to decreased viability. The complexes 61 and 62 displayed substantial cytotoxicity towards MCF-7 and HeLa cells. Importantly, complex 62 (IC₅₀ = 1.00 ± 0.09 μM) displayed much stronger inhibitory activity than cisplatin (IC₅₀ = 3.19 ± 0.02 μM) towards MCF-7 cells. Besides, complex 61 (IC₅₀ = 20.28 ± 2.09 μM) exhibited much stronger cytotoxic activity than cisplatin (IC₅₀ = 53.50 ± 0.07 μM) against the HeLa cell line. The presence of s Co(iii) metal center in the complexes was seen as a significant factor in their observed cytotoxicity towards the tested cell lines in comparison to the uncomplexed ligands. Complex 62 showed somewhat increased cytotoxicity compared to complex 61 against both the cell lines. A comparison of the activity of complex 62 with previously reported cobalt complexes containing different ligands showed that complex 62 exhibited better activity.⁶⁹

Fig. 27. Chemical structures of the cobalt(iii) complexes with thiosemicarbazone ligands (61 and 62), as reported by Manikandan and coworkers.¹⁹⁷.

Thiosemicarbazones are a biologically active class of sulphur-donor ligands with potential to coordinate several transition metal ions. The bioactivity of thiosemicarbazones is determined by the type of the heteroatom containing a ring in addition to the structure of the thiosemicarbazone part.¹⁹⁸ Several suitable modifications in the chemical structures of metal complexes of thiosemicarbazones lead to the development of compounds with different specificities and action mechanisms. A number of metal complexes of thiosemicarbazones have caused apoptosis in many cancer cells.¹⁹⁶ Sobiesiak and coworkers¹⁹⁹ demonstrated the anticancer properties of two cobalt(ii) complexes containing thiosemicarbazone ligands (Fig. 28: complexes 63 and 64) against HUVEC (human umbilical vein endothelial cells), HeLa and K562 (human immortalized myelogenous leukemia) cells. The authors observed that both complexes had antitumour efficacy against all the cell lines. Complex 63 had higher activity against K562 and HeLa cells with IC₅₀ values of 30 ± 3 μM and 90 ± 15 μM, respectively. However, complex 64 showed a higher activity in HUVEC and K562 cells, with IC₅₀ values of 50 ± 4 μM and 50 ± 27 μM, respectively. Complex 63 was found to be more active against K562, whereas complex 64 was found to be more active in HUVEC and K562 than cisplatin. Overall, the findings revealed that these complexes can serve as promising leads for future research in designing and developing anticancer cobalt complexes.

Fig. 28. Chemical structures of the cobalt(ii) complexes with thiosemicarbazone ligands (63 and 64), as reported by Sobesiek and coworkers.¹⁹⁹.

The discussion in this part leads to the conclusion that cobalt complexes with different thiosemicarbazone ligands have demonstrated excellent anticancer effects towards several human cancer cell lines. Furthermore, in comparison to cisplatin, some cobalt complexes have demonstrated many folds higher cytotoxic activities. Additionally, some cobalt complexes showed the ability of overcoming the resistance of cancer cells. Consequently, it is reasonable to assume that some of the complexes will eventually result in the discovery of potential anticancer alternatives.

4.7. Cobalt complexes with active pharmaceuticals

Metal complexes containing active pharmaceuticals as ligands are currently a growing topic of investigation in inorganic medicinal chemistry.^200,201 Developing metal complexes of active pharmaceuticals is basically a drug repurposing strategy, which aims at identifying new therapeutic potencies of the already well-established drugs.^202,203 Mefenamic acid is a NSAID known for the inhibition of cyclooxygenase-1 and 2, and its anti-inflammatory effects. Mefenamic acid exhibits neuroprotection and also ameliorates cognitive damage in both the in vitro and in vivo models of Alzheimer's disease.^204,205 In view of the therapeutic importance of mefenamic acid, Kovala-Demertzi et al.²⁰⁶ documented the in vitro cytotoxicity of cobalt(ii) complex containing mefenamic acid (Fig. 29: complex 65) against MCF-7, T24, A-549 and L-929 (mouse fibroblast cell line) cells. The complex was highly cytotoxic against the T24 cell line with an IC₅₀ value of 2.70 × 10⁻⁵ M (molar concentration), which is considerably lesser than that of cisplatin (IC₅₀ = 4.17 × 10⁻⁵ M).

Fig. 29. Chemical structure of the cobalt(ii) complex containing mefenamic acid (65), as reported by Kovala-Demertzi et al.²⁰⁶.

DOX is a clinically used chemotherapeutic agent. It is used for breast cancer treatment, and also finds uses in combination chemotherapeutic regimens with other anticancer drugs.²⁰⁷ In view of the therapeutic benefits of doxorubicin, Jabłońska-Trypuć and coworkers²⁰⁸ reported the effects of cobalt(ii) complexes of doxorubicin (Fig. 30: Complex 66) on the viability, apoptosis, cell cycle and proliferation of MCF-7 cells. MCF-7 cells were treated with various amounts of DOX and complex 66 for 24 hours. The complex reduced cancer cell viability in a dose-dependent pattern. The overall results revealed that doxorubicin complexed with cobalt may be a more effective chemotherapeutic agent for breast cancer treatment than DOX alone.

Fig. 30. Chemical structure of the cobalt(ii) complex of doxorubicin (66), as reported by Jabłońska-Trypuć and coworkers.²⁰⁸.

Flufenamic acid is characterized by its high polymorphism, with several structurally distinct modifications.²⁰⁹ Its chemical structure is unique among fenamates,²¹⁰ particularly due to the inclusion of a trifluoromethyl group, a trait that has garnered considerable attention in drug design rationales.²¹¹ The inclusion of fluorine-containing substituents in molecules is associated with beneficial chemical and biological properties.²¹² Molecules with fluorine containing substituents, such as flufenamic acid, have shown potential in enhancing the pharmacokinetics and bioavailability of drugs.²¹³ Research indicates that repositioning flufenamic acid could be promising for the treatment of Bartter syndrome.²¹⁴ In view of these interesting physico-chemical properties of flufenamic acid, Fang et al.²¹⁵ investigated of the advancement of anti-cancer stem cell drugs, focusing on the cytotoxicity and immunogenicity of cobalt(iii)–cyclam complexes (Fig. 31: complex 67) including flufenamic acid. The cytotoxicity of complex 67 on HMLER (bulk cancer cell line) and HMLER-shEcad (bulk breast cancer cell line) cell lines was investigated. The complex 67 was toxic to HMLER-shEcad and HMLER cells at sub-micromolar concentrations, with breast CSCs (cancer stem cells) being somewhat more sensitive. Notably, complex 67 was 24 and 31 folds more toxic to breast CSCs than salinomycin and cisplatin, respectively. Flufenamic acid had a 171-fold lower efficacy than complex 67 towards HMLER or HMLER-shEcad cells, but trans-dichloro(cyclam)–cobalt(iii) chloride, complex 68 (Fig. 31), was non-toxic (IC₅₀ value > 100 μM). When administered in 1/2 ratio, the combination regimen of flufenamic acid and complex 68 exhibited up to 89-fold loss in efficacy against HMLER and HMLER-shEcad cells as compared to complex 67. The complex 67 was more effective (p < 0.05) in destroying breast cancer cells and CSCs in contrast to a combination of its separate components. To evaluate therapeutic profiles, the cytotoxic activity of complex 67 against HEK-293 (human embryonic kidney cells) cells was examined. The complex 67 had a lower potency against HEK-293 cells (IC₅₀ value = 2.49 ± 0.36 μM) than against HMLER and HMLER-shEcad cells. This suggested that complex 67 had the ability to destroy bulk breast cancer cells and breast CSCs more effectively than normal cells. Under low attachment conditions lacking serum, the cultivation of breast CSCs leads to the formation of three-dimensional multicellular masses known as mammospheres.²¹⁶ The potential of a drug to decrease viability or mammosphere formation is a good indicator of its potential for translating into clinical settings. Therefore, the ability of complex 67 to suppress mammosphere development was evaluated by using an inverted microscope. The addition of complex 67 to the single-cell suspensions of HMLER-shEcad cells significantly decreased the quantity (69%) and mammosphere size (Fig. 32). Under identical conditions, salinomycin and cisplatin inhibited mammospheres similarly to complex 67. In particular, salinomycin and cisplatin decreased the mammosphere number by 54% and 50%, respectively. Treatment with complex 68 or flufenamic acid (at their IC₂₀ values for 5 days) had no significant effect on the quantity or size of mammospheres. To test the potential of complex 67 for diminishing the viability of mammospheres, the colorimetric resazurin-based reagent TOX8 was used. The IC₅₀ value of complex 67 was submicromolar, 69 and 50 folds lesser than that of salinomycin and cisplatin, respectively. Flufenamic acid or complex 68 had no detectable mammosphere potency (IC₅₀ > 133 μM). Taken together, the mammosphere experiments revealed that complex 67 is effective at reducing mammosphere development and viability, and that its ability is substantially larger than salinomycin (standard anti-breast CSC drug). Complex 67 also prevented the viability and formation of three-dimensional mammospheres at sub-micromolar concentrations. Under identical conditions, complex 67 had greater inhibitory and cytotoxicity effects on mammospheres than salinomycin and cisplatin combined. Mechanistic investigations revealed that complex 67 caused DNA damage, decreased cyclooxygenase-2 production, and activated caspase-dependent cell death. Breast CSCs after treatment with complex 67 showed damage in terms of molecular patterns consistent with immunogenic cell death. Overall, this research indicated enormous potential of cobalt complexes with important active pharmaceuticals in developing potential anticancer agents.

Fig. 31. Chemical structures of the cobalt(iii)–cyclam complexes (67 and 68), as reported by Fang et al.²¹⁵.

Fig. 32. (A) Quantitative assessment of the formation of mammospheres with HMLERshEcad cells that are untreated and treated with IC₂₀ concentrations of complexes 67 and 68, flufenamic acid, salinomycin and cisplatin for 5 days. (B) Illustrative bright-field images (×10) of HMLER-shEcad mammospheres without treatment and with treatment using IC₂₀ concentrations of complexes 67 and 68 and flufenamic acid for 5 days. Reprinted with permission from ref. 215. Copyright 2024 John Wiley and Sons.

An assessment of the research studies reviewed in this sub-section indicated that cobalt complexes with active pharmaceuticals as ligands showed some exciting anticancer activities towards several cancer cell lines. Most of the reported complexes exhibited better activity than cisplatin, and can be further explored as anticancer agents. Thus, additional studies are recommended for developing cobalt complexes that have high biological activity with better therapeutic profiles, which might lead to anticancer drugs with desired efficacy.

4.8. Cobalt complexes with natural products

The design of metal complexes of natural products (in modified or unmodified forms) as ligands offers promise for the development of safe and effective anticancer agents. By connecting naturally occurring compounds such as Schiff bases, anthraquinones, and naphthoquinones with metal centers, metal complexes with enhanced bioactivities can be developed.²¹⁷ Several cobalt(ii) and cobalt(iii) complexes of natural products such as coumarin, curcumin, quercetin, and their derivatives have shown interesting anticancer profiles.^218–220

Metal complexes of coumarin derivatives have fascinated researchers owing to their interesting therapeutic profiles. Giriraj and coworkers²¹⁹ documented the in vitro cytotoxicity and toxicities of four cobalt(iii) complexes (Fig. 33: complexes 69–72) containing substituted acetyl coumarin Schiff bases towards MCF-7 and A-549 cancer cells and non-cancerous HUVECs. The complexes showed promising anticancer activity towards the tested cell lines. Interestingly, the complexes were more active than cisplatin towards cancerous cells and less toxic than cisplatin towards normal cells. Besides, these complexes induced cancer cell death via apoptosis. Sunitha et al.²²¹ documented the anticancer properties of cobalt(ii) complex (Fig. 34: complex 73) against MCF-7 and K562 cells. The complex showed promising anticancer activity towards both the cell lines with an IC₅₀ value less than 10 μg mL⁻¹. Recently, Shebl and coworkers²²² have reported the anticancer properties and toxicity of cobalt(ii) complex of coumarinyl–pyrazolyl–thiazole thiosemicarbazone (Fig. 35: complex 74) against HepG2 and MCF-7 cells and HFB4 (normal human melanocyte cell line) cells. The complex was active against both HepG2 (IC50 = 17.18 ± 0.96 μM) and MCF-7 (18.68 ± 1.24 μM) cancer cells. Interestingly, the complex was minimally toxic to normal HFB4 cells.

Fig. 33. Chemical structures of the cobalt(iii) complexes, as reported by Giriraj and coworkers.²¹⁹.

Fig. 34. Chemical structure of the cobalt(ii) complex, as reported by Sunitha et al.²²¹.

Fig. 35. Chemical structure of the cobalt(ii) complex of coumarinyl–pyrazolyl–thiazole thiosemicarbazone, as reported by Shebl and coworkers.²²².

Quercetin is a biologically active natural product.²²³ Metal complexes of quercetin are thought to enhance its biological properties. The studies on the anticancer properties of cobalt complexes of quercetin or its derivatives are very scarce. In one study, Kalinowska et al.²²⁰ synthesized a cobalt(ii) complex of quercetin (Fig. 36: complex 75) and investigated the cytotoxic activity of the complexes towards HaCat cells. The complex was non-cytotoxic towards HaCat cells.

Fig. 36. Chemical structure of the cobalt(ii) complex of quercetin, as reported by Kalinowska et al.²²⁰.

A critical analysis of this section reveals that several cobalt(ii) and cobalt(iii) complexes of coumarin and its derivatives have displayed promising anticancer activity towards several cancer cell lines. Interestingly, several complexes have shown better cytotoxicity towards cancer cells than cisplatin and more selectivity towards normal cells than cisplatin. It is important to mention that the cobalt complex of quercetin did not show any significant anticancer activity. Therefore, further studies are recommended to fully explore the potential of cobalt complexes of coumarin derivatives as anticancer agents. Additionally, more studies are required to investigate cobalt complexes of quercetin derivatives as anticancer agents.

4.9. Organometallic anticancer cobalt complexes

Recent research studies indicate increasing attention towards the rational design of anticancer organometallic complexes with focus on avoiding the drawbacks encountered with currently market-available platinum-based anticancer medications.²²⁴ However, the investigations reporting the anticancer properties of half-sandwich organometallic cobalt complexes are very scarce.⁴¹ Half-sandwich metal complexes of 2,2-bipyridine or 1,10-phenantroline ligands have displayed interesting in vitro and in vivo anticancer and antimetastatic properties. Such complexes are thought of as possible substitutes to current anticancer chemotherapeutics.^{225–227,230–232} Machado et al.³⁷ investigated the cytotoxic activities of cobalt(iii)–cyclopentadienyl complexes (Fig. 37: 76–79) against HCT116 (human colorectal adenocarcinoma cell line), A2780 (human ovarian carcinoma), MDA-MB-231 and MCF-7 cells within a range of concentrations from 0.1 to 50 μM for 48 hours of incubation. In the A2780 cell line, a concentration-dependent reduction in cell viability for every complex was observed. Fascinatingly, complexes 77–79 also led to a concentration-dependent reduction in MCF-7 and HCT116 cell viability; however, the loss of viability of HCT116 cells was greater than that of MCF-7 cells. The order of cytotoxicity of the complexes towards the most sensitive cell line, A2780, was 79 > 77 = 78 > 76, but for HCT116 cells, the order was 78 > 79 > 77 > 76, and for MCF-7 cells, only complex 79 was substantially cytotoxic (IC₅₀ = 10.2 μM). Complex 79 was not cytotoxic to MDA-MB-231 cells, despite a small loss in cell viability (IC₅₀ > 50 μM). Complex 79 had the lowest relative IC₅₀ against A2780 cells (4.7 μM) in comparison to other complexes, indicating a strong antiproliferative activity against the cell line.

Fig. 37. Chemical structures of the cobalt(iii)–cyclopentadienyl complexes (76–79), as reported by Machado et al.³⁷.

Shridhar and coworkers²²⁸ reported the anticancer properties of organometallic half-sandwich Co(ii)–arene complexes (Fig. 38: complex 80) towards A-549 and A2780 cells. The complex was more active than cisplatin (IC₅₀ = 17.0 ± 6.1 μM) towards A-549 cells (IC₅₀ = 15.4 ± 2.8 μM). However, the complex displayed lower activity than cisplatin towards A2780 cells. The mechanistic studies indicated that the complex induced cancer cell death via both apoptosis and necrosis. Recently, Aguado et al.²²⁹ have documented the anticancer properties of semi-sandwich cobalt(iii) complexes with 1-amidino-2-thiourea ligands (Fig. 39: complexes 81–85) against HeLa and HepG2 cells. The complexes showed high cytotoxicity towards HeLa and HepG2 cell lines with IC₅₀ values ranging from 0.23 ± 0.038 to 0.31 ± 0.020 μM, and 0.27 ± 0.034 to 0.80 ± 0.045 μM, respectively. The complexes induced cancer cell death via substantial upsurge in intracellular ROS.

Fig. 38. Chemical structure of the half-sandwich Co(ii)–arene, as reported by Shridhar and coworkers.²²⁸.

Fig. 39. Chemical structures of the semi-sandwich cobalt(iii) complexes with 1-amidino-2-thiourea ligands, as reported by Aguado et al.²²⁹.

The discussion in this section leads to the conclusion that organometallic cobalt complexes have shown encouraging anticancer profiles. Even some complexes have shown anticancer activities better than cisplatin. However, further in vitro and in vivo investigations are required to discover novel ligand systems whose cobalt coordination may result in chemical systems with enhanced therapeutic characteristics.

4.10. Photoactive anticancer cobalt complexes

Chemotherapeutic drugs suffer from certain serious deleterious effects towards normal cells and tissues of the body. Photo-activation (light-stimulated activation) of pro-drugs is a promising approach to amplify the selectivity of otherwise toxic drugs. Photo-activation leads to the production of cytotoxic species, which do not exhibit any toxicity under dark conditions. Currently, several photodynamic porphyrin-containing drugs including Photofrin are used in clinical settings. However, the issues of their extended photosensitivity and toxicity towards liver cells hamper their use.²³⁰ To evade the disadvantages associated with classical organic PDT (photodynamic therapy) drugs, transition metal complexes of different ligand architectures have shown great promise as photoactive cytotoxic agents towards several cancer cell lines.^231,232 Several cobalt(ii) and cobalt(iii) complexes have shown promising in vitro photo-cytotoxicity.^233–235 Das et al.²³⁶ documented the in vitro photocytotoxicity of several anthraquinone-based cobalt(ii) complexes (Fig. 40: complexes 86–90) towards HeLa and A-549 cells. The complexes were highly photocytotoxic towards HeLa (IC₅₀ = 1.6–4.2 μM) and A-549 (IC₅₀ = 2.1–6.1 μM) cancer cell lines. Interestingly, the complexes displayed minimum cytotoxicity towards the tested cells under dark conditions (IC₅₀ > 70 μM). The photocytotoxic mechanism of the complexes was established from flow cytometric experiments by using complex 90. It was revealed that the complex generated ROS under visible light irradiation, which caused the death of cancer cells. Recently, Dutta and coworkers²³⁷ reported the photocytotoxicity of several cobalt(iii) complexes (Fig. 41: complexes 91–96) containing flavonoids, chrysin and silibinin towards HeLa and A-549 cells. All the complexes were stable in dark and under light irradiation in the solution phase. All the complexes displayed profound photocytotoxicity towards the tested cell lines. However, complexes 95 and 96 showed impressive activity towards HeLa and A-549 cells under irradiation with visible light with very low IC₅₀ values (2.3–3.4 μM) and phototoxicity index (15–30). Importantly, the complexes were much less toxic towards HPL1D (normal lung epithelial cells) cells. The complexes induced apoptotic mode of cell damage in the cancer cells. The generation of ROS and singlet oxygen species by the irradiated complexes was responsible for the photocytotoxicity of the complexes. The overall results indicated impressive photocytotoxic properties of the complexes in general and complexes 95 and 96 in particular with emphasis on the future in vivo investigations of these complexes for anticancer PDT applications. The same research group in another research²³⁸ demonstrated the light-amplified cytotoxicity of several cobalt(ii)–catecholate complexes (Fig. 42: complexes 97–100). The complexes were remarkably stable in solution under dark conditions and upon light irradiation. Complexes 98 and 100 displayed substantial cytoxicity towards A-549 cells. Interestingly, the cytotoxic activity of these two complexes amplified significantly upon light irradiation at 660 nm (red light) and 808 nm (near infrared) laser light for 5 minutes. More importantly, the complexes displayed minimum toxicity to normal NIH-3T3 fibroblasts. The improvement of cytotoxicity of the complexes was due to the production of cytotoxic singlet oxygen upon red/near-infrared light irradiation.

Fig. 40. Chemical structures of the anthraquinone-based cobalt(ii) complexes, as reported by Das et al.²³⁴.

Fig. 41. Chemical structures of the cobalt(iii) complexes, as reported by Dutta and coworkers.²³⁷.

Fig. 42. Several cobalt(ii)–catecholate complexes, as reported by Dutta et al.²³⁸.

An overall assessment of the research studies discussed in this section indicates a promising potential of cobalt(ii) and cobalt(iii) complexes as photoactive anticancer complexes. The remarkable photocytotoxicity of cobalt complexes and minimum cytotoxicity under dark conditions along with no or minimum toxicity towards normal cells dictates further investigations of these complexes towards other cancer cell lines. Besides, the results prompt in vivo investigations of the reported photoactive cobalt complexes for anticancer PDT effects.

4.11. Mixed ligand and mixed metal anticancer cobalt complexes

Mixed ligand complexes of transition metals have fascinated researchers owing to their DNA binding ability by involving several types of interactions. Such complexes are also known to cleave DNA on account of their inherent chemical, photochemical and electrochemical reactivity.^239–241 Several mixed ligand cobalt(ii) and cobalt(iii) complexes have displayed interesting anticancer properties against several cancer cell lines.^242–244 In this direction, Gençkal et al.²⁴⁵ documented the anticancer properties of Co(ii) complex (Fig. 43: complex 101) containing quercetin and diimine (1,10-phenanthroline or 2,2′-bipyiridine) as ligands towards A-549, PC-3, HeLa and MCF-7 cell lines. The complex was moderately active towards the tested cell lines. The cancer cell viability of the complex was lower than 50% only in the case of PC-3 cells at a dosage of 50 μM. In another important research investigation, Deka and coworkers²⁴⁶ demonstrated the anticancer properties and toxicities of several cobalt(iii) complexes (Fig. 44: complexes 102–107) containing mixed ligands from 8-hydroxyquinolines and phenanthroline bases towards MCF-7, HT29, U87MG (glioblastoma), A-549, NCIH23 (lung adenocarcinoma), A2780, RPMI (squamous cell carcinoma), PLC/PRF/5 (hepatocellular carcinoma) and HeLa cancer cell lines, and normal HEK-293 cells. The complexes displayed stability in aqueous buffer solutions containing ascorbic acid as a reducing agent. It was revealed by the cytotoxicity studies that complex 102 did not display any significant activity (IC₅₀ > 100 μM) towards the tested cell lines. Complexes 103–107 were active against the tested cell lines with IC₅₀ values ranging from 11.3 ± 0.6 to 70.4 ± 3.5 μM. However, complex 107 was the most active complex with IC₅₀ values ranging from 2.8 ± 0.1 to 13.8 ± 0.7 μM. This complex was even more active than cisplatin towards MCF-7, NCIH23 and RPMI cells. Interestingly, all the complexes were less toxic than cisplatin towards normal HEK-293 cells. The mechanism of cell death induced by the complexes was due to apoptosis, which was assigned to the production of ROS. The research report indicated promising properties of the complexes in general, proving complex 107 as an important lead for further investigations.

Fig. 43. Chemical structure of the Co(ii) complex containing quercetin and diimine (1,10-phenanthroline), as reported by Gençkal et al.²⁴⁵.

Fig. 44. Chemical structure of the cobalt(iii) complexes containing mixed ligands from 8-hydroxyquinolines and phenanthroline bases, as reported by Deka and coworkers.²⁴⁶.

Mixed metal complexes are multifunctional agents containing two or more metal atoms/ions by virtue of which these complexes acquire improved biological properties including anticancer.²⁴⁷ The integration of two or more types of cytotoxically active metal centers within a complex often enhances anticancer activity due to varied interactions of the metals with several biological targets. The enhancement of anticancer properties is sometimes due to the enhanced physicochemical characteristics of the resulting mixed metal complexes. Mixed metal cobalt(ii) and cobalt(iii) complexes have shown interesting anticancer properties against different cancer cell lines.^248,249 In view of these facts, Nagy and coworkers²⁵⁰ reported the anticancer properties of two mixed-metal complexes containing cobalt(iii) and ruthenium(ii) metal centers (Fig. 45: complexes 108 and 109) towards HeLa, MCF-7, HCT116 and MDA-MB-231 cell lines. Both the complexes displayed interesting anticancer activities. Complex 108 was more active than cisplatin towards MDA-MB-231cells, whereas complex 109 was more active than cisplatin towards both MCF-7 and MDA-MB-231 cells. Recently, Gavrikov et al.²⁵¹ have reported anticancer properties and toxicity of two mixed-metal complexes containing cobalt(ii) and yttrium(iii) metal centers (Fig. 46: complexes 110 and 111) against T98G (glioblastoma cell line), HBL-100 (human breast epithelial cell line), HBL-100/Dox (doxorubicin-resistant human breast epithelial cell line) and Mel IS (cutaneous melanoma cell line), and toxicity towards PBK (normal human cutaneous fibroblasts). The complexes were active against HBL-100 and HBL-100/Dox cell lines. Besides, complex 111 showed pronounced activity against Mel IS and T98G cells. Interestingly, the complexes were also non-toxic to PBK cells. The selective cytotoxicity was attributed to the interactions of the complexes with important molecular targets including chaperone proteins, nucleolin and nucleophosmin, which are generally over-expressed in cancer cells playing crucial roles in their metabolic processes. The anticancer properties of the complexes were also revealed through in vivo studies using Mel IS xenografts.

Fig. 45. Chemical structures of the mixed-metal complexes containing cobalt(iii) and ruthenium(ii) metal centers, as reported by Nagy and coworkers.²⁵⁰.

Fig. 46. Chemical structures of the mixed-metal complexes containing cobalt(ii) and yttrium(iii) metal centers, as reported by Gavrikov et al.²⁵¹.

A critical analysis of this section revealed the promising potential of mixed-ligand and mixed-metal cobalt complexes as anticancer agents against several cancer cell lines. It is interesting to note that some mixed ligand cobalt complexes have shown activity better than cisplatin with selectivity towards normal cells. It is pertinent to mention here that the mixed-metal complexes bearing cobalt(iii) and ruthenium(ii) metal centers also showed better activity than cisplatin towards several cancer cell lines. Specifically, the metal complexes bearing cobalt(ii) and yttrium(iii) metal centers were appreciably active towards several cancer cell lines including HBL-100/Dox cells. Besides, the complexes were non-toxic to PBK cells. Overall, the reported mixed-ligand and mixed-metal cobalt complexes look promising with regard to their anticancer properties towards a plethora of cancer cell lines.

5. Nanoformulations of anticancer cobalt complexes

The delivery of drugs via nanoparticles is becoming increasingly popular in the pharmaceutical industry. Nanoformulations enhance biodistribution and pharmacokinetics of drugs. Besides, drugs in nanoforms have improved solubility, dose proportionality and oral bioavailability, and reduced adverse effects along with increased patient compliance.²⁵² From the time of the licensing of liposomal doxorubicin in 1995, many nanoformulations, using dendrimers, polymer–drug conjugates and inorganic nanoparticles have undergone clinical testing.²⁵³ Exciting results have been obtained by the administration of anticancer metal complexes within a wide array of nanoparticle vectors.^254,255 In view of the significance of nanoparticles in delivering active pharmaceutical ingredients, Abbasi et al.²⁵⁶ synthesized a mononuclear cobalt(iii) Schiff base complex (Fig. 47: complex 112) and used it as a precursor for the preparation of cobalt oxide nanoparticles by solid-state thermal decomposition. The cytotoxicity of the complex 112 and its metal-oxide nanoparticle against MKN-45 (human gastric cell line) cancer cell line was determined. The findings demonstrated that complex 112 and its cobalt nanoparticle exhibited dose–response-dependent anticancer efficacy. The cell viability of nano metal oxides was determined in vitro towards MKN-45 cells and compared with the cytotoxicity of complex 112. The IC₅₀ value of complex 112 was 10.851 ± 1.384 μM and that of the nanoparticle was 7.899 ± 1.908 μM, which indicated a strong anti-proliferative effect of the nanoparticles against MKN-45 cells. Besides, the complex and its nanoparticle exhibited a notable inhibitory effect towards the growth and morphology of MKN-45 cells. In addition, the complex caused selective apoptosis in cancer cells. Overall, the complex 112 and its nanoparticle caused cytoxicity in a dose-dependent pattern.

Fig. 47. Chemical structure of the mononuclear cobalt(iii) Schiff base complex 112, as reported by Abbasi et al.²⁵⁶.

PLGA (poly lactic-co-glycolic acid) has shown exciting properties such as biocompatibility, biodegradability and controlled drug release.²⁵⁷ The modification of PLGA with PEG (polyethylene glycol) brings in promising nanoparticle properties such as prolonged blood circulation time and reduced immunogenicity.^258,259 In view of these facts, Talebi and coworkers²⁶⁰ reported the cytotoxic activity of cobalt(iii) complex 113 and its corresponding nanoconjugate (Fig. 48) against A2780 and A2780-CisR (cisplatin-resistant human ovarian carcinoma) cells. A di-block polymer, PLGA–PEG, was used as the nanocarrier for achieving higher efficacy and controlled release of the complex. SEM was used for gaining insights into the morphology of the nanoconjugate of complex 113. The nanoconjugate particles displayed well-defined spherical shapes with sizes in the range of 81–389 nm (diameter) (Fig. 49). The EDX studies indicated the presence of cobalt, which confirmed the successful conjugation of complex 113 in the nanoformulation (Fig. 49). DLS experiments indicated 191 nanometric diameter for the nanoconjugate particles (Fig. 49). The anticancer screenings showed that the complex 113 (IC₅₀ = 488.6 ± 1.5 μM) had no significant antiproliferative effects towards A2780. However, the nanoconjugate of the complex had an IC₅₀ value of 160.4 ± 4.5 μM, much lower than that of the complex and almost equivalent to cisplatin. The IC₅₀ of complex 113 against A2780-CisR cells was also evaluated, and the RF (resistance factor) was calculated by taking the ratio of IC₅₀ for the resistant and wild-type cell lines. The results indicated that cisplatin had very little effect on A2780-CisR cells, resulting in an RF of 9.3. Nevertheless, the cytotoxicity of complex 113 (IC₅₀ = 683.2 ± 3.0 μM) and its nanoconjugate (IC₅₀ = 747.5 ± 0.1 μM) was found to be greater than that of cisplatin (IC₅₀ = 1239.2 ± 3.5 μM) by a factor of around 2, with RF values for complex 113 and the nanoconjugate of 1.4 and 4.6, respectively. The findings from this research report suggested potential nano-biomedical use of cobalt complexes and their nanoconjugates for the treatment of cancer.

Fig. 48. Chemical structure of the cobalt(iii) complex, as reported by Talebi and coworkers.²⁶⁰.

Fig. 49. Glimpse of the: (A) morphology, (B) elemental analysis, and (C) size distribution of the nanoconjugate of complex 113. Reprinted with permission from ref. 260. Copyright 2019 John Wiley and Sons.

Reducing toxicity and increasing target selectivity is the primary goal of every drug design rationale. The co-assembly of polydiacetylenes with DMPC finds uses for optimizing the surface charge, size and stability of nanoparticles. This delivery system finds applications for the controlled and sustained release of active pharmaceuticals.²⁶¹ Taking advantage of these properties, Mounica et al.²⁶² explored the antiproliferative effects of two half-sandwich cobalt(iii)-pentamethylcyclopentadienyl complexes (Fig. 50: 114 and 115) against A-549 and HeLaS3 (clonal derivative of parent human cervical carcinoma) cancer cell lines. The complex 114 demonstrated significant cytotoxicity (IC₅₀ = 0.5 μM) against both A-549 and HeLaS3 cells; however, the complex was moderately toxic to normal human lung fibroblast cells (IC₅₀ = 6.02 μM). The IC₅₀ values indicated that complex 114 has significant cytotoxic effects on the lung (IC₅₀ = 0.56 μM) and cervical (IC₅₀ = 0.55 μM) cancer cell lines. Complex 115 showed notable cytotoxicity towards HeLaS3 cells (IC₅₀ = 9.81 μM) but was less effective against A-549 cells (IC₅₀ = 27.2 μM). Notably, both complexes 114 and 115 exhibited higher cytotoxic activity than cisplatin towards both cell lines. The toxicity of 114 towards healthy fetal lung fibroblast cells was eleven folds lower than that towards cancer cells, suggesting a higher specificity for cancer cells. However, further research is necessary to minimize the toxicity of these complexes to develop them as potential anticancer drugs. Complex 114 was encapsulated into polydiacetylene-phospholipid nanoformulations, and it was observed that the toxicity of the encapsulated complex significantly decreased towards healthy cells. Nevertheless, the nanoformulation was less active towards A-549 and HeLaS3 cells as compared to the naked complex.

Fig. 50. Chemical structures of the half-sandwich cobalt(iii)-pentamethylcyclopentadienyl complexes 114 and 115, as documented by Mounica et al.²⁶².

The discussion of the research studies in this sub-section highlights that nanoformulations of cobalt complexes exhibit several remarkable properties unattainable with molecular cobalt complexes. These include selectivity, and both improved and extended therapeutic effects, which are essential criteria for qualifying as a therapeutic entity. Consequently, there is a strong anticipation that research in this field will continue to grow, which might lead to groundbreaking results towards the development of effective anticancer agents.

6. Synergism of anticancer cobalt complexes with standard anticancer drugs

Synergism often produces better results than the combined individual results of the synergized entities. The phenomenon of synergism has been used in pharmacology, medicine, biochemistry and physiology for enhancing desired pharmacological effects and reducing the undesired ones. The application of synergism in drug development is aimed at increasing desired properties and decreasing undesired therapeutic features of the synergized drugs. Synergism helps in increasing biological activity, reducing toxicity and the onset of drug resistance.²⁶³ In view of the importance of synergism in drug discovery, Hopff and coworkers studied the anticancer profiles of cobalt(iii) salen complex (Fig. 51: complex 116), displaying promising anticancer properties.²⁶⁴ Profound apoptotic properties against acute lymphoblastic leukemia and Burkitt-like lymphoma cells were displayed by the complex. The ability of complex 116 to overcome resistance to daunorubicin by NDau cells along with understanding of its action mechanism made this complex a potent candidate for use in cancer therapy. The participation of the complex in the central pathway of apoptosis was observed. This was revealed by an independence on CD95, a dependence on caspase-3, and loss of mitochondrial membrane depolarization in Nalm6 (lymphoblastic leukemia) cells upon treatment with complex 116. The synergetic effects of complex 116 with vincristine and daunorubicin were very impressive. With such combinations, lesser concentrations of complex 116 were required for effectiveness towards leukemia. Besides, normal leucocytes were not affected by complex 116. These results were highly relevant for the investigation of cobalt–salen metal complexes in response to the fact that there are no reports on the bioactivities of cobalt–salen complexes against leukemia cells. In another interesting research, Uprety et al.²⁶⁵ reported the anticancer properties of urease mimetic cobalt(iii) complexes (Fig. 52: complexes 117–120) towards A549 and MCF-7 cells. The complexes were moderately active towards the tested cell lines. The authors went on to study the impact of extracellular alkalinization by the complexes 117–120 on the efficiency of doxorubicin, which is a weakly basic anticancer drug. This drug combination caused improved apoptosis in A549 cells, which was seen from the increased caspase 3/7 activity. Overall, the complexes displayed interesting urease-mimicking anticancer properties and synergistically cooperated with doxorubicin for enhanced anticancer effects.

Fig. 51. Chemical structures of the cobalt(iii) salen complex, as reported by Hopff and coworkers.²⁶⁴.

Fig. 52. Chemical structures of the urease mimetic cobalt (iii) complexes, as reported by Uprety et al.²⁶⁵.

Acute myelogenous leukemia remains a challenging disease with relatively low disease-free survival rates of 40–50%, even among younger patients who undergo intensive treatment.²⁶⁶ Imatinib, a tyrosine kinase inhibitor, has significantly altered the management of CML (chronic myeloid leukemia cell line). Nevertheless, the issues of acquired resistance and inability to withstand complete cytogenetic remission have tempered the initial excitement.²⁶⁷ A promising approach to enhance treatment effectiveness involves using agents with different mechanisms of action in combination regimens, which leads to synergistic or additive effects. Notably, the concurrent administration of imatinib and cisplatin has shown a synergistic effect in causing the inhibition of A-549 cells. Besides, increased DNA fragmentation in K562 cells has been reported with this combination regimen.^268,269 Cobalt alkyne complexes, also known as acetylenehexacarbonyldicobalt complexes, have already demonstrated anticancer properties against human leukaemia and lymphoma cells.^270,271 Keeping this in view, Ott et al.²⁷² assessed the impact of cobalt(ii) alkyne complexes with propargylic acid esters (Fig. 53: complexes 121–123) on HL60, LAMA-84 (human chronic myeloid leukemia cell line) and CML-T1 (chronic myeloid leukemia cell line) cells. The inhibition of cell growth (IC₅₀ values starting at 9.5 μM) and apoptosis induction (up to a 5.5-fold increase in single-stranded DNA at 50 μM concentration) by individual agents were moderate. Imatinib and cobalt complexes (121–123) were administered at sub-optimal concentrations (imatinib: 0.1 μM and cobalt complexes: 10 μM) both as single agents and in combination. Synergetic effects were observed against LAMA-84 and CML-T1 cells by the combination of imatinib with complexes 121 and 123, and complex 123, respectively. Additive effects were noted for all other combination regimens. The most significant outcomes were observed with complexes that incorporated ligands from nonsteroidal anti-inflammatory drugs, specifically acetylsalicylic acid and naproxen.

Fig. 53. Chemical structures of the cobalt(ii) alkyne complexes with propargylic acid esters, as reported by Ott et al.²⁷².

An overall critical assessment of this section indicates that cobalt complexes synergized with standard anticancer drugs such as vincristine, daunorubicin, doxorubicin and imatinib and produced impressive results. Therefore, the study of synergism of cobalt complexes with other anticancer agents of natural or synthetic origin may lead to the development of some effective drug combination regimens, and therefore, such studies are highly recommended.

7. Mechanistic insights

Medicinal chemists have always been fascinated by investigations of action mechanisms of therapeutic agents. Mechanistic research provides valuable insights for designing safe and effective medicaments. Cobalt complexes discussed in the preceding sections of this paper have demonstrated interesting anticancer profiles towards different human cancer cell lines. Several cobalt complexes have exhibited selectivity to cancer cells and minimum toxicity against normal cell lines. Besides, several cobalt complexes have shown significant efficacy towards cancer cells that are otherwise resistant to several market available anticancer drugs. It is important to mention here that many cobalt complexes behave differently from anticancer platinum complexes with respect to their mechanisms of action.

ROS are highly reactive chemical species (groups or molecules) containing odd electrons. ROS are continuously produced and removed in biological systems. Cancer cells have higher ROS levels as compared to healthy cells because of oncogenic activation, amplified metabolism, and mitochondrial dysfunction. Low quantities of ROS promote the survival of cancer cells by activating growth factors and receptor tyrosine kinases, which drive cell cycle progression.²⁷³ ROS levels also regulate chronic inflammation, a main cause of cancer. High ROS levels can limit tumour development by activating cell-cycle inhibitors.^274,275 Higher ROS levels can cause cell death and senescence through macromolecular damage. Chemotherapeutic drugs often cause cancer cells to die by increasing the ROS levels.^276,277 Several cobalt complexes have been shown to produce ROS, which acts as their anticancer mechanisms of action. Zhao et al.⁸⁸ reported the anticancer action mechanism of complex 3 (Fig. 4) towards the T24 cell line. The complex caused early apoptosis by the blockage of cell cycle in the G1 phase via the mitochondrial pathway by the generation of ROS and Ca²⁺ ions, and a decreased membrane potential in T24 cells. Besides, complex 3 activated caspases 3 and 9 in cancer cells. The results from western blot investigations revealed that complex 3 affected apoptosis-related protein expressions, which further confirmed the involvement of mitochondrial pathway. In another important investigation, Zhang et al.¹³¹ documented the anticancer activity of complex 13 (Fig. 9) towards SK-OV-3, BEL-7404, HeLa229, T24 and MGC-803 cancer cell lines. The complex significantly caused arrest of cell cycle in T24 cells at the S phase, which, in turn, induced cell death. The mechanism of apoptosis in T24 cells treated with complex 13 was examined through the detection of ROS, measurement of calcium concentration (intracellular), and observation of caspase-9/3 activity. The results showed a clear correlation between the three factors, namely mitochondrial membrane potential loss, ROS production, and increase in intracellular Ca²⁺, all of which led to the activation of caspase-9/3 through a pathway involving mitochondrial dysfunction. In another study, Zhang et al.¹³² documented the cytotoxicity of complexes 14–16 (Fig. 10) against various cancer cell lines including T24, BEL-7404, HepG2, HeLa, MGC-803, SKOV-3, HL-7702 and WI-38. The mechanism of action of complex 14 was explored, and it was shown to induce apoptotic death in T24 cells through the arrest of G1 cell cycle. Additional studies indicated that complex 14 triggered the overproduction of ROS, leading to apoptosis mediated by the mitochondria. Recently, Ma and coworkers²⁷⁸ reported the generation of ROS as the mechanism of cytotoxicity of salophen cobalt(iii) complexes (Fig. 54: complexes 124–126) towards A2780, A2780cis-R and HL60 cells. The cytotoxicity was determined by the efficiency of cellular uptake and ROS generation. The complexes with longer ester alkyl chains had greater cellular uptake (ethyl, 124 < propyl, 125 < butyl, 126). Interestingly, the anticancer activity correlated well with ROS generation. Complex 124 induced only few ROS and had low cytotoxicity, whereas complexes 15 and 126 displayed profound anticancer activity as a result of high ROS generation (Fig. 55: complexes 124–126).

Fig. 54. Chemical structures of the salophen cobalt(iii) complexes (124–126), as reported by Ma and coworkers.²⁷⁸.

Fig. 55. Effect of complexes 124–126 (at a dosage of 20 μM) on ROS generation in A2780cis cells. Data pertaining to one representative experiment are depicted: (a) control, (b) incubation with 124, (c) incubation with 125, (d) incubation with 126, and (e) incubation with cisplatin (5 μM). Reprinted with permission from ref. 278. Copyright 2023 John Wiley and Sons.

Apoptosis is the process of planned death of cells in living organisms, characterized by certain cellular changes.²⁷⁹ Cells undergo many alterations during apoptosis, including blebbing, shrinkage, nuclear fragmentation, chromatin condensation and chromosomal DNA fragmentation. Apoptotic pathways result in the death of cells through several mechanisms. Ahamad and coworkers⁹⁰ performed DAPI staining to study the apoptotic potential of complex 5 (Fig. 5) in HeLa cells. Chromatin condensation during apoptosis was found to be a defining marker of nuclear alteration. HeLa cells were subjected to different concentrations of complex 5. Upon examination of the cells using a fluorescent microscope fitted with a DAPI filter, it was observed that the control cells barely had any type of condensation as compared to the test complex. The radiantly shrunk chromatin bodies, and nuclear blebbings were observed. In addition to nuclear changes, the complex-treated groups also showed shrinking morphology, another significant hallmark of apoptosis. Li et al.¹⁴¹ documented the anticancer activities of complexes 24–28 (Fig. 16) against HeLa, A-549, HT29, SMMC7721 and HepG2 cells. In subsequent experiments, the complexes demonstrated enhanced inhibition of COX-2, NF-kB and iNOS. The complexes also caused apoptosis in HepG2 cells via the mitochondrial pathway, as evaluated by staining with various fluorescent reagents such as PI, DAPI, DCFH-DA and Mito-Tracker Green. Concurrently, the complexes caused up-regulation of the expression levels of caspase-3 and Bax, while causing down-regulation of Bcl-2 expression. In another investigation, Mounica et al.²⁶² studied the antiproliferative activities of complexes 114 and 115 (Fig. 50) inside a polydiacetylene-phospholipid nanoformulation. To determine the mode of action, HeLaS3 and A-549 cells were tested with complexes 114 and 115 at their IC₅₀ concentrations for 24 hours. The cells were then stained with 200 μM of AO (acridine orange) and 100 μM of EB (ethidium bromide) and observed for morphological changes using fluorescence microscopy. Morphological alterations in HeLaS3 and A-549 cells were detected, including membrane blebbing, nuclear condensation, and the development of tiny apoptotic bodies. As a result, the AO/EB staining experiment demonstrated that the complexes primarily foster early and late apoptosis cells in cervical and lung cancer cells.

Ferroptosis involves iron-catalysed generation and build-up of lipid peroxides, which eventually lead to cell death in a programmed manner. Lipid peroxidation is brought about by the action of oxidants, such as ROS, on polyunsaturated fatty acids.^280,281 Hydroxyl radical is known for its high reactivity and mobility as an ROS, and is particularly impactful towards lipids.^282,283 Conspicuously, the phenomenon of ferroptosis can also be activated by certain intrinsic pathways, which may involve the exhaustion or inhibition of glutathione peroxidase 4, or some extrinsic pathways, which may inhibit the cystine/glutamate transporter.²⁸⁴ After the overactivity of glutathione-dependent anti-oxidant defence mechanisms, lipid peroxidation turns unstrained, which ultimately leads to cell death by ferroptosis.^285,286 In view of these mechanistic understandings, ferroptosis-linked cell death may be brought by chemical species that generate hydroxyl radicals or eradicate/reduce the anti-oxidant defence mechanisms. Recently, Montesdeoca et al.²⁸⁷ have documented the anticancer and ferroptosis-inducing properties of a Co(iii) polypyridine sulfasalazine complex (Fig. 56: complex 127) against CT-26 (mouse colon carcinoma), MCF-7, Hep G2, THP-1 (human leukemia) and PT-45 (human pancreatic adenocarcinoma) cancer cells and normal cells, GM-5657 (non-cancerous human fibroblasts), MEF (mouse embryonic fibroblast) and HEK-293. The complex displayed promising anticancer activities towards all the tested cancer cells with selectivity towards normal cells. The complex was further investigated against CT-26 cancer cells. After uptake into CT-26 cells, the complex mainly accrued in the mitochondria and triggered the generation of hydroxyl radicals and lipid peroxides (Fig. 57). These processes eventually caused the death of cancer cells by ferroptosis. The complex eradicated several monolayer cancer cells in addition to colon carcinoma multicellular tumour spheroids.

Fig. 56. Chemical structure of the Co(iii) polypyridine sulfasalazine complex, as reported by Montesdeoca et al.²⁸⁷.

Fig. 57. (A) Accumulation of the complex 127 in cell organelles of the CT-26 cells after 4 hours of incubation. (B) Quantitative assessment of cell viability upon pre-incubation with ˙OH (50 mM, d-mannitol), ¹O₂ (5 mM, sodium azide), or ˙O₂⁻ (5 mM, 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt monohydrate) specific scavengers, which overpower the potential of the complex 85 to produce cytotoxic ROS species, treatment with the IC₅₀ concentration of the complex 85 (1.26 μM) and determination of the cell viability. (C) Fluorescence microscopic images of the CT-26 cells upon co-incubation with the IC₅₀ concentration complex 127 (1.26 μM) and the ˙OH (3′-p-(hydroxyphenyl)fluorescein, λ_ex = 460–490 nm, λ_em = 517–527 nm), ¹O₂ (singlet oxygen sensor green, λ_ex = 460–490 nm, λ_em = 517–527 nm), or ˙O₂⁻ (dihydroethidium, λ_ex = 545–580 nm, λ_em = 617 nm) specific fluorophores. Reprinted with permission from ref. 287. Copyright 2024 John Wiley and Sons.

Autophagy is a crucial homeostatic mechanism that helps in degrading and recycling cellular materials.²⁸⁸ Stimulating autophagy in illness is gaining popularity, particularly for removing protein clumps that cause neurodegeneration.

The involvement of autophagy in cancer is complicated and varies depending on the tumour stage, tumour biology and microenvironment of the tumour cells and tissues. Primarily, the process of autophagy leads to the development of autophagosomes, which encapsulate cellular cargoes and fuse with lysosomes. Lysosomal hydrolases then degrade the contents of the autophagosome.²⁸⁹ Autophagy is a type-II cell death process; therefore, its activation is crucial during tumour cell death caused by metallodrugs.^290–292 Wang et al.¹³⁴ documented the cytotoxicity of three cobalt(ii) complexes 18–20 (Fig. 13) towards SK-OV-3/DDP, SK-OV-3 and HL-7702 cancer cells. To assess the impact of complexes 18 (0.32 μM) and 20 (0.32 μM) on the death of cancer cells, their potential to trigger autophagy was evaluated by measuring the mRFP-eGFP-LC3 (tfLC3) levels in SK-OV-3/DDP cells. Following a 24-hour incubation, both the complexes 18 and 20 exhibited a significant increase in autophagosome and autolysosome counts. Furthermore, the presence of complexes 18 and 20 led to the expression of a set of autophagy-related proteins, namely p62, beclin1, and LC3 II/I. Notably, the expression levels of these proteins were elevated in cells that were treated with complex 18 with respect to the cells treated with complex 20. Consequently, complex 18 was expected to have more pronounced autophagy-inducing properties than complex 20, as suggested by mechanistic studies.

DNA is one of the primary biological targets for a large number of anticancer metallodrugs. The extent and nature of interaction between metallodrugs and DNA are closely linked to the biological and pharmaceutical effects of the former.^293–295 Understanding the modes of binding between metal complexes and DNA can shed light on their biochemical mechanisms, which is crucial for the development of potent chemotherapeutic drugs. Recent studies have reported several cobalt(ii) complexes that are potential DNA binders, and also exhibit DNA cleavage activity.^295–298 Gowdhami et al.⁹¹ studied the cytotoxicity of two cobalt complexes 6 and 7 (Fig. 6) against MCF-7 and A-549 cells. Fluorescent staining indicated that the complexes triggered cell death in MCF-7 and A-549 cells through binding to DNA and consequent damage, mitochondrial membrane potential alteration and oxidative stress. In another investigation, Fan et al.¹⁹⁴ documented the in vitro cytotoxicity of two cobalt(ii) complexes 59 and 60 (Fig. 26) towards A-549, A-549/CDDP and MCF-7 cancer cells. DNA binding investigations revealed that the complexes 59 and 60 exhibited effective binding to DNA by a groove-binding mode, which was ascertained by analysis through electronic absorption, CD and fluorescence spectroscopy. The binding strength of the complexes followed the order of complex 60 > complex 59. In another research, Manikandan and coworkers¹⁹⁷ documented the cytotoxicity of cobalt(iii) complexes 61 and 62 (Fig. 27) towards HeLa and MCF-7 cells. Fluorescence spectroscopy was employed to assess the DNA binding interaction of the complexes, indicating that both the complexes were capable of DNA intercalation. Notably, complex 62 exhibited a higher DNA binding strength than complex 61, which was attributed to the phenyl substitution in the thiosemicarbazone structure of the former. Additionally, gel electrophoresis assays confirmed that both complexes cleaved plasmid pBR322 DNA. The protein binding assessment conducted through fluorescence spectroscopy revealed an increased binding affinity correlating with the substitution of a phenyl group at thiosemicarbazone moiety's terminal nitrogen.

The overall analysis of this sub-section indicated that wide ranges of mechanisms of action have been observed for anticancer cobalt complexes bearing a plethora of ligand systems. The main mechanisms of action displayed by the active cobalt complexes included ROS generation, apoptosis, autophagy, ferroptosis and DNA binding. In a nutshell, the investigations into the rational drug design on anticancer cobalt complexes are still in infancy. Nevertheless, this field is witnessing considerable research efforts, and it is expected that forthcoming studies will unveil novel molecular leads along with their mechanisms of action.

8. Pharmacologically significant anticancer cobalt complexes

Drug design strategies aim to design and develop new therapeutic agents with improved activity, reduced toxicity and other benefits over existing drugs.²⁹⁹ This review solely emphasizes on the anticancer profiles of cobalt complexes with several ligand frameworks. Through this review, different types of cobalt complexes with exciting efficacies towards various human cancer cell lines have been identified (Table 1). Several complexes (pharmacologically significant anticancer cobalt complexes) have shown stronger anticancer activities than renowned anticancer medicaments such as cisplatin, carboplatin, salinomycin and 5-fluorouracil, which strongly advocate for their future investigations including in vivo and clinical studies.

Table 1. Comparison of the anticancer profiles of the pharmacologically significant anticancer cobalt complexes with standard anticancer drugs.

Ligand type	Complex number	IC50 value of complexes in M μM−1 nM−1	Tested cell lines	Standard anticancer drug	IC50 value of standard anticancer drug	Ref.
Schiff bases	1	7.63 ± 0.94	HepG2	Cisplatin	17.54 ± 1.52	88
		13.61 ± 1.32	A-549		18.92 ± 1.51
		6.12 ± 0.79	Wi-38		19.35 ± 0.41
		18.24 ± 1.12	HL-7702		20.51 ± 1.45
	2	5.71 ± 2.21	A-549		18.92 ± 1.51
		6.12 ± 0.79	Wi-38		19.35 ± 0.41
	3	11.65 ± 0.79	MGC-803		19.64 ± 0.78
		14.69 ± 0.96	HepG2		17.54 ± 1.52
		7.59 ± 0.34	T24		20.32 ± 1.34
		15.81 ± 1.56	Wi-38		19.35 ± 0.41
	4	10.41 ± 1.06	MGC-803		19.64 ± 0.78
		10.98 ± 1.96	HepG2		17.54 ± 1.52
		3.23 ± 0.86	T24		20.32 ± 1.34
		11.66 ± 2.09	A-549		11.66 ± 2.09
		16.57 ± 1.32	SK-OV-3		25.87 ± 0.67
		9.41 ± 0.78	Wi-38		19.35 ± 0.41
		11.03 ± 1.07	HL-7702		20.51 ± 1.45
	5	20.29	A-549		40	90
		7.339	HeLa		16
	6	08.56 ± 0.07	MCF-7		12.47 ± 0.04	92
		19.53 ± 0.06	A-549		22.38 ± 0.21
		52.16 ± 0.06	3T3		115.12 ± 0.09
	7	03.55 ± 0.08	MCF-7		12.47 ± 0.04
		10.78 ± 0.18	A-549		22.38 ± 0.21
		85.15 ± 0.09	3T3		115.12 ± 0.09
	8	18.03 ± 2.66	A-549/CDDP		44.79 ± 2.75	300
	9	5.4 ± 0.06	MCF-7		15.10 ± 0.05	103
		5.83 ± 0.04	A-549		16.79 ± 0.08
	10	5.04 ± 0.03	MCF-7		15.10 ± 0.05
		5.7 ± 0.05	A-549		16.79 ± 0.08
	11	4.62 ± 0.05	MCF-7		15.10 ± 0.05
		5.41 ± 0.04	A-549		16.79 ± 0.08
	12	5.6 ± 0.04	MCF-7		15.10 ± 0.05
		6.54 ± 0.07	A-549		16.79 ± 0.08
Quinoline derivatives	13	7.04 ± 0.06	T24	Cisplatin	14.05 ± 0.03	131
	14	7.00 ± 0.06	T24		15.93 ± 0.06	132
		13.50 ± 0.03	BEL-7404		24.87 ± 0.29
	15	13.22 ± 0.04	T24		15.93 ± 0.06
	17	0.25 ± 0.06	BEL-7404		13.06 ± 1.01	126
		0.12 ± 0.15	HepG2		14.02 ± 1.41
		0.80 ± 0.21 nM	HeLa		17.03 ± 1.05
		0.94 ± 1.03	MCF-7		14.18 ± 1.03
	18	1.88 ± 0.35	SK-OV-3		10.04 ± 1.22	134
		0.32 ± 0.09	SK-OV-3/DDP		>50
	19	3.56 ± 0.49	SK-OV-3		10.04 ± 1.22
		0.72 ± 0.24	SK-OV-3/DDP		>50
	20	5.49 ± 0.85	SK-OV-3		10.04 ± 1.22
		1.08 ± 0.42	SK-OV-3/DDP		>50
Carbonyl groups	24	19.12 ± 0.17	HeLa	Cisplatin	29.37 ± 0.26	141
		22.56 ± 0.43	A-549		39.55 ± 0.18
		10.20 ± 0.41	HepG2		34.46 ± 0.26
		14.33 ± 0.20	SMMC7721		40.16 ± 0.19
		20.34 ± 0.12	HT29		36.86 ± 0.32
	25	23.16 ± 0.23	HeLa		29.37 ± 0.26
		30.19 ± 0.57	A-549		39.55 ± 0.18
		16.22 ± 0.52	HepG2		34.46 ± 0.26
		12.15 ± 0.65	SMMC7721		40.16 ± 0.19
		26.36 ± 0.19	HT29		36.86 ± 0.32
	26	26.23 ± 0.56	A-549		39.55 ± 0.18
		18.62 ± 0.60	HepG2		34.46 ± 0.26
		20.11 ± 0.31	SMMC7721		40.16 ± 0.19
		26.02 ± 0.31	HT29		36.86 ± 0.32
	27	24.74 ± 0.37	HeLa		29.37 ± 0.26
		21.25 ± 0.32	A-549		39.55 ± 0.18
		10.07 ± 0.25	HepG2		34.46 ± 0.26
		14.68 ± 0.56	SMMC7721		40.16 ± 0.19
		33.78 ± 0.60	HT29	5-Fluorouracil	36.86 ± 0.32
	35	6.8 (±3.2)	MDA-MB-231		9.6 (± 0.3)	152
Polypyridyls	37	61.0 ± 8.8	U2OS	Carboplatin	174.5 ± 8.7	154
	38	37.5 ± 1.1	U2OS		174.5 ± 8.7
	39	32.5 ± 0.6	U2OS		174.5 ± 8.7
	44	10.89 ± 0.55	A-549	Cisplatin	20	159
		1.97 ± 0.1	MDA-MB-231		7.5
	45	7.63 ± 0.4	A-549		20
		0.98 ± 0.05	MDA-MB-231		7.5
Thiosemicarbazones	62	1.00 ± 0.09	MCF-7		3.19 ± 0.02	197
		20.28 ± 2.09	HeLa		53.50 ± 0.07
	63	30 ± 3	K562		150 ± 30	199
	64	50 ± 27	K562		150 ± 30
		50 ± 4	HUVEC		95 ± 43
Active pharmaceuticals	65	2.70 × 10−5 ± 1.7 M	T24	Salinomycin	41.7 × 10−6 M	206
		0.27 ± 0.03	HMLER		2.57 ± 0.02
		0.18 ± 0.003	HMLER-shEcad		5.65 ± 0.30
		0.27 ± 0.02	Mammosphere		13.50 ± 2.34
		0.27 ± 0.03	HMLER		11.43 ± 0.42
		0.18 ± 0.003	HMLER-shEcad		4.23 ± 0.35
		0.27 ± 0.02	Mammosphere		18.50 ± 1.50
Natural products	69	5.28 ± 2.29 to	MCF-7 and A-549	Cisplatin	28.04 ± 1.32 to 45.18 ± 3.01	219
	70	13.25 ± 2.58
	71	6.29 ± 2.80 to
	72	10.89 ± 1.97
Organometallic half-sandwich	80	15.4 ± 2.8	A-549	Cisplatin	17.0 ± 6.1	228
Mixed ligands, 8-hydroxyquinoline and phenanthroline	107	4.4 ± 0.2 to 8.0 ± 0.4	MCF-7, NCIH23 and RPMI	Cisplatin	5.7 ± 0.3 to 10.0 ± 0.5	246
Nanoformulations	113	683.2 ± 3.0	A2780-CisR	Cisplatin	1239.2 ± 3.5	262
	113-loaded nanoparticles	747.5 ± 0.1	A2780-CisR		1239.2 ± 3.5
	114	0.56 ± 2.6	A-549		53 ± 4.3
		0.55 ± 1.5	HeLaS3		27.2 ± 2.5
		6.02 ± 3.1	IMR-90		>100
		27.2 ± 1.4	A-549		53 ± 4.3
	115	9.81 ± 0.8	HeLaS3		27.2 ± 2.5
		38.2 ± 0.6	IMR-90		>100

A variety of Schiff base cobalt complexes (1–4) were more selective for cancer cells (MGC-803, HepG2, T24, A-549 and SK-OV-3) than cisplatin. Interestingly, complex 3 showed better anticancer effects towards the T24 cancer cell line than cisplatin. It is worthy to note that the toxicity of complex 3 against normal human cells (Wi-38 and HL-7702) was similar to that of cisplatin.⁸⁸ These findings indicated that complex 3 might be a possible future anticancer metallodrug subject to further investigations in in vivo and clinical studies. Another interesting Schiff base-containing cobalt complex 5 showed greater anticancer activity than cisplatin towards both HeLa and A-549 cell lines. The cobalt complexes 6 and 7 bearing Schiff base ligands displayed pronounced cytotoxicity towards MCF-7, A-549 and 3 T3 cells. Complex 7 was shown to be more effective than complex 6 in inducing antiproliferative activity in MCF-7 and A-549 cells. However, both complexes caused toxicity in normal 3T3 cells, albeit at extremely high doses, almost 2 to 4 times than that of MCF-7 and A-549 cells. Interestingly, the complexes destroyed cancer cells at doses similar to or lower than cisplatin.⁹¹ The cobalt–Schiff base complex 8 showed comparable cytotoxic activity to cisplatin in HeLa cells.⁹⁵ The IC₅₀ value of complex 8 in cisplatin-resistant cells was roughly 2.48-fold lower than that of cisplatin. The cobalt–Schiff base complexes 9–12 were highly potent towards MCF-7 and A-549 cells with an IC₅₀ value lesser than that of cisplatin.¹⁰³

Cobalt complexes containing quinoline-derived ligands have shown promising anticancer properties. The cobalt complex of quinoline-derived ligand (complex 13) demonstrated much stronger antiproliferative activity in comparison to cisplatin against SK-OV-3/DDP and SK-OV-3 cancer cells.¹³² The cobalt complexes of quinoline-based ligands (complexes 14–16) had the strongest anticancer activity towards T24 tumour cell line, with IC₅₀ ranging from 7.00 to 16.70 μM. The complexes demonstrated preference for T24 tumour cells over the normal cells HL-7702 and WI-38. Interestingly, complex 14 induced a higher percentage of apoptotic cell death than cisplatin.¹³² Another important cobalt complex of the quinoline-derived ligand (complex 17) was highly cytotoxic against human HeLa cells and HeLa xenograft tumour formation. The complex 17 was around 300 folds more active than cisplatin towards the tested cancer cells.¹²⁶ The cobalt(ii) complexes of 8-methoxyquinoline (complexes 18–20) displayed higher anticancer activities than cisplatin against SK-OV-3/DDP and SK-OV-3 cancer cells.¹³⁴

Cobalt carbonyl complexes have demonstrated exciting cytotoxic activities. The cobalt-carbonyl complexes 24–28 were significantly active against HepG2 and SMMC7721 cells, with IC₅₀ ranging from 10.07–16.22 μM. These values were comparable to or even better than the values for cisplatin.¹⁴¹ The cobalt-carbonyl complexes (29–36) were active towards MCF-7 and MDA-MB-231 cells. The potency of these complexes was within the potency range of cisplatin and 5-fluorouracil.¹⁵²

Cobalt complexes bearing polypyridyl ligands also exhibit intriguing cytotoxicity. The complexes 40–42 displayed high efficacy against U2OS, HepG2 and GMO5757 cancer cells.¹⁵⁶ The cytotoxicity of these complexes was equal to that of cisplatin and carboplatin. The most active cobalt(ii) complex (41) entered U2OS cells, penetrated the nucleus, caused genomic DNA damage, and promoted caspase-dependent cell death in a p53-independent way. This research emphasized the enormous potential of di-nuclear cobalt(ii) complexes as oxidative metallonucleases and cytotoxic agents. The cobalt complexes 43–46 containing polypyridyl ligands were active towards A-549 and MDA-MB-231 cells. Complexes 44 and 45 outperformed cisplatin; however, the cytotoxic activity of 43 and 46 was comparable to cisplatin.¹⁵⁹ Cobalt complexes bearing macrocyclic ligands have displayed interesting cytotoxic activities. Macrocyclic cobalt complexes 47 and 48 were cytotoxic against Hep3B, MCF-7 and HeLa cells. In addition, both complexes were less toxic to PBMC than doxorubicin and 5-fluorouracil.¹⁷⁰

The in vitro anticancer activities of cobalt complexes with thiosemicarbazone ligands (59 and 60) towards A-549, A-549/CDDP and MCF-7 cell lines were studied. Complex 60 was found to be more cytotoxic than complex 59, and both exhibited greater anticancer activity than the parent ligands. Interestingly, the two complexes displayed increased activity towards A-549/CDDP and MCF-7 cells at several tested concentrations. Remarkably, complex 60 was significantly more effective against A-549/CDDP cells.¹⁹⁴ The cobalt complex (62) of a thiosemicarbazone ligand demonstrated higher cytotoxic activity than cisplatin in MCF-7 and HeLa cells.¹⁹⁷ Interesting anticancer properties were exhibited by thiosemicarbazone containing cobalt complexes, 63 and 64. Complex 63 was more active against K562, whereas complex 64 was found to be more active in HUVEC and K562 than cisplatin.¹⁹⁹

Cobalt complexes containing active pharmaceuticals as ligands have shown remarkable anticancer profiles towards different cancer cell lines. Cobalt complex of mefenamic acid (65) displayed promising anticancer properties. Complex 65 was highly cytotoxic against T24 cell line, exhibiting nearly double the potency as that of cisplatin.²⁰⁶ The cytotoxic and immunogen-activating profiles of a cobalt(iii)–cyclam complex with flufenamic acid (67) were reported. The complex demonstrated sub-micromolar activity against breast CSCs that were grown in monolayers, which was 24 and 31 folds higher than that of salinomycin and cisplatin, respectively. Remarkably, complex 67 was 69 and 50 folds more potent than salinomycin and cisplatin, respectively, against breast CSC mammospheres cultured in three dimensions.²¹⁵ The complexes 69–72 containing coumarin Schiff bases as ligands reported by Giriraj et al. were more active than cisplatin towards MCF-7 and A-549 cells.²¹⁹ The organometallic half-sandwich complex reported by Shridhar and coworkers was more active than cisplatin towards A-549 cancer cells.²²⁸ Mixed ligand complex 107 bearing 8-hydroxyquinoline and phenanthroline as ligands was found to be much more active than cisplatin towards MCF-7, NCIH23 and RPMI cancer cells.²⁴⁶

Nanoformulations of cobalt complexes described in this paper have also exhibited exciting anticancer profiles. The cytotoxic activity of cobalt complex 113 and its nanocarrier towards A2780 and A2780-CisR cell lines was determined. The effect of cisplatin on A2780-CisR cells was minimal, with an RF value of 9.3. In contrast, complex 113 and its nanocarrier showed a cytotoxic potency greater than cisplatin by approximately a factor of 2, with RF values of 1.4 and 4.6, respectively.²⁶⁰ The antiproliferative effects of two cobalt(iii) half-sandwich complexes (114 and 115) towards A-549 and HeLaS3 cancer cells were determined. Complex 114 exhibited significant cytotoxicity towards both cell lines, while also being moderately toxic to healthy human lung fibroblast cells. The IC₅₀ values suggested that complex 114 was notably cytotoxic to lung and cervical cancer cells. Alternatively, complex 115 was particularly cytotoxic to cervical cancer cells. Remarkably, both complexes showed higher cytotoxicity than cisplatin in treating lung and cervical cancer cells.²⁶²

A complete list of the pharmacologically significant anticancer cobalt complexes along with their IC₅₀ values against the screened cell lines is given in Table 1.

An analysis of Table 1 reveals that most of the anticancer cobalt complexes that are pharmacologically significant have Schiff bases as ligands. This indicates that Schiff bases are active pharmacophores in the context of the development of cytotoxic cobalt complexes. Besides, quinoline-based ligands, ligands containing carbonyl groups, polypyridyls and thiosemicarbazones are also very important pharmacophores for the development of cytotoxic cobalt complexes. However, none of the macrocyclic cobalt complex showed superior anticancer profiles to standard anticancer drugs.

Overall, ligands and ligand systems such as Schiff bases, quinolines, carbonyl groups, polypyridyl ligands, macrocyclic ligands, thiosemicarbazones, and active pharmaceuticals among others form stable complexes with cobalt, exhibiting significant cytotoxicity. It can be understood that the influence of the ligands and the coordination sphere are crucial factors determining the anticancer effects of these cobalt complexes. The design and development of new cobalt complexes, inspired by the promising anticancer properties of the aforementioned ligand systems, appears to be a viable strategy.

The future development of these complexes is promising due to their potent anticancer properties, minimal toxicity to normal cells, and varied action mechanisms. The prospect of investigating these systems on additional cell lines, and the in vivo evaluation of the effective complexes, represents a significant step forward in establishing anticancer cobalt complexes.

9. Comparison of anticancer cobalt complexes with complexes of other first transition series metals

Doubtlessly, several cobalt complexes discussed in this review have demonstrated impressive anticancer profiles. A number of complexes have exhibited promising anticancer activities towards cancer cells with non-toxicity towards normal ones. In order to have a clear understanding of the anticancer effects brought about by the complexation of cobalt center with different types of ligands, a comparison of the anticancer properties of cobalt complexes with similarly structured complexes of other metals from first transition series was made (Table 2). The other first transition series metals used for the comparison include manganese, nickel, copper and zinc. It can be seen from Table 2 that complexes 73 and 129 (Fig. 58) were more active than similarly structured manganese, nickel, copper and zinc complexes, and copper and zinc complexes, respectively. Besides, complexes 49 and 128 (Fig. 58) were more active than similarly structured zinc and nickel complexes, respectively. In addition, the complexes 63, 64, 101 and 130 (Fig. 58) displayed activities at par with those of similarly structured complexes of nickel and manganese complexes. However, complexes 5, 63, 64, 74, 101 and 128 were less active than similarly structured copper complexes. Overall, cobalt complexes have displayed either comparable or better anticancer activities than manganese, nickel and zinc complexes. However, in terms of anticancer activities, cobalt complexes somewhat lag behind copper complexes. From the analysis of the research studies cited in Table 2 and others, it becomes important to analyse the factors that make cobalt complexes potent with respect to manganese, nickel and zinc complexes, and also identify the factors that make them less potent than copper complexes. The analysis can lead to data that might help in the development of effective anticancer cobalt complexes.

Table 2. Comparison of the anticancer properties of cobalt complexes with similarly structured complexes of other first transition series metals.

S. No.	Ligands used	Complex number of the cobalt complex	Other first transition series metal used in the complex	Tested cell lines	Whether other first transition series complex is more active or less active than the cobalt complex	Ref.
1	Schiff base ligand	5	Copper	A-549 and HeLa	Copper complex was more active than complex 5	90
2	Macrocyclic ligand	49	Zinc	HeLa	Complex 49 was more active than the zinc complex	161
3	1-[Amino(thioxo)methyl]-5-hydroxy-3-methyl-1H pyrazole	63 and 64	Copper and nickel	HeLa and K562	Complexes 63 and 64 were less active than copper complexes, and had comparable activity to that of nickel complexes	199
4	Coumarin derivative	73	Manganese, nickel copper and zinc	MCF-7 and K-562	Complex 73 was many folds more active than manganese, nickel, copper and zinc complexes	221
5	Coumarinyl–pyrazolyl–thiazole thiosemicarbazone	74	Nickel and copper	HepG2	Both nickel and copper complexes were more active than complex 74	222
				MCF-7
6	Quercetin and diimine as ligands	101	Nickel and copper	A-549, PC-3, HeLa and MCF-7	Copper complexes were more active than 101, but had comparable activity to that of nickel complex	245
7	Hydrazone of 2-(2-(2,4-dihydroxybenzylidene)hydrazinecarbonyl)pyridine-1-oxide	128	Nickel, copper and zinc	MDA-MB-231 and SKOV-3	Complex 128 was less active than copper complex, however, complex 128 was much more active than nickel and zinc complexes	73
8	Thio-bis(benzimidazole)	129	Copper and zinc	CEM, MCF-7, HeLa and G-361	Complex 129 was more active than copper and zinc complexes	39
9	Sodium valproate and 1,10-phenanthroline as ligands	130	Manganese	HeLa and HepG2	Comparable activity	243

Fig. 58. Chemical structures of the cobalt complexes (128, 129 and 130) containing hydrazone of 2-(2-(2,4-dihydroxybenzylidene)hydrazinecarbonyl)pyridine-1-oxide, thio-bis(benzimidazole), sodium valproate and 1,10-phenanthroline as ligands, respectively.

10. Prevailing challenges and future perspectives

Despite the recent advances in science and technology, cancer treatment still remains a big challenge.³⁰¹ Because of the fact that the efficacy of current anticancer medications is limited, there are more recorded fatalities than survivals. An overview of the prevailing challenges, and future outlooks and perspectives of research towards the development of effective anticancer cobalt complexes is shown in Fig. 59.

Fig. 59. Outline of the prevailing challenges and future outlooks of research in the design and development of effective anticancer cobalt complexes.

Cancer cells are known to develop resistance to anticancer therapies, reducing their efficacy over time. Furthermore, anticancer drugs are pricey for the general public. Currently, there are no established standards for developing new active anticancer metal complexes. While some studies have determined SARs (structure–activity relationships), no general standards exist. It is still a mystery to predict which complexes are likely to be effective and need additional examination in the foreseeable future. Several physical and chemical properties of metallodrugs including low solubility and hydrolytic instability hamper their development as effective drugs. Despite significant progress in understanding genetic and molecular aetiology of cancer cells and tissues, appropriate treatment strategies remain elusive. Given these facts, it is critical to hasten the development of effective anticancer medicines.³⁰²

Metal complexes have the potential to be exploited for developing effective anticancer therapies. Metal complexes, such as cisplatin, its analogues, and some ruthenium complexes, play an important role in modern cancer therapy. Encouraging targeting and activation tactics to find new drugs that overcome the drawbacks of cisplatin therapy can be practiced. The pharmaceuticals that may be developed should have low side/adverse effects and wide-ranging activities, along with the ability to overcome drug resistance.³⁰³ Understanding how ligands influence the reactive nature of transition metal ions/atoms, as well as how metal ions/atoms alter ligand characteristics, is critical for identifying target locations and for enhancing the biological activity. DFT (density functional theory), multinuclear polarization transfer, NMR (nuclear magnetic resonance) spectroscopy, and high-resolution electrospray-mass spectrometry are some of the techniques that can be exploited for developing metallodrugs with better therapeutic profiles. More significant SARs can be established by applying DFT, multinuclear polarization transfer, NMR spectroscopy, and high-resolution electrospray-mass spectrometry to better understand the biochemical reactivity of metal complexes. It is decisive to research the biochemistry of metal complexes in physiologically relevant contexts such as biological screenings and investigations.

The integration of metal complexes with nanoparticles can lead to targeted action and reduced adverse effects. Nanoparticle-based drug delivery approaches represent innovative methods for transporting and targeting anticancer drugs. Investigating the targeted delivery of cobalt complexes to specific sites using nanoparticles, which are adorned with cell-specific antibodies, could prove advantageous. Moreover, it is essential to devise methods that ensure the transport of complexes directly to their designated action sites, including mechanisms triggered by pH (potential of hydrogen) changes. Drug combinations have demonstrated synergistic effects in treating cancer. Innovative therapeutic combinations may emerge from integrating cobalt complexes with other drugs. Presently, computational tools and theoretical analyses, including Percepta Platform, AutoDock, and Lipinski's rule, can forecast the therapeutic efficacy of drugs prior to their synthesis. It is vital to develop cobalt complexes that are molecularly screened for optimal bioavailability, solubility, minimal side effects, and enhanced efficacy. Future research should leverage software modelling tools to identify biological targets and enhance the structural diversity of new cobalt complexes. The unique chemical properties of cobalt and the structural flexibility of its complexes have drawn attention as a tool for ongoing studies into possible cancer treatments. Comprehending the processes behind the anticancer effects of cobalt complexes would facilitate the development of more specialized and effective pharmaceuticals.

11. Conclusions

Developing safe and highly active anticancer medications is the foremost priority for medicinal chemists. Researchers around the world are tirelessly working for the progress of effective cancer treatment modalities. The scientific attention towards the design and development of anticancer cobalt complexes has shown an impressive increase during the last decade. Therefore, this article aimed to critically review the developments in anticancer cobalt complexes. The results of anticancer research on cobalt complexes containing ligand systems such as Schiff bases, quinolines, carbonyl groups, polypyridyls, macrocycles, thiosemicarbazones, active pharmaceuticals, etc. were reviewed. It is important to mention here that the pharmacologically significant cobalt complexes identified through this review have displayed superior or equivalent therapeutic benefits to well-known anticancer drugs such as cisplatin, carboplatin and 5-fluorouracil. Therefore, these pharmacologically significant cobalt complexes should be further examined in vivo in animal models, and both in vitro and in vivo on other cancer cells lines and tumour models, respectively. Interestingly, several cobalt complexes showed potential to overcome cancer cell resistance, displayed high selective cytotoxic activities against cancer cells, reduced toxicities to normal cells, and operated through various mechanisms such as ROS generation, autophagy, and apoptosis. It is quite surprising to note that despite exhibiting exciting anticancer activities, cobalt complexes have been catching only little interest of the researchers. Therefore, international collaboration between different allied disciplines is essential to develop safe cobalt complexes for cancer treatment. Eradicating cancer, a disease that severely affects the lives of patients and their well-being, is of utmost importance, and cobalt-based metallo-anticancer drugs represent a hopeful avenue in this endeavour.

Author contributions

Conceptualization: Waseem A. Wani, Afzal Hussain and Mohmed F. Alajmi. Project administration: Waseem A. Wani, Afzal Hussain and Mohmed F. Alajmi. Supervision: Waseem A. Wani, Afzal Hussain, Mohmed F. Alajmi and Samira Amir. Visualization: Akhtar Hussain Malik, Jahangir Ahmad Rather and Waheed Ahmad Khanday. Writing – original draft: Azharudin Khursheed, Nuzhat Khursheed, Nusrat Rashid, Abdul Haleem Wani and Jahangir Ahmad. Writing – review and editing: Iqbal Hussain and Prince Firdous Iqbal.

Conflicts of interest

“There are no conflicts to declare”.

Data availability

This review does not include any primary research results, software or code. No new data have been generated or analysed in any part of this review.