Supramolecular Coordination Complexes for Synergistic Cancer Therapy.

ConspectusSupramolecular coordination complexes (SCCs) are predictable and size-tunable supramolecular self-assemblies constructed through directional coordination bonds between readily available organic ligands and metallic receptors. Based on planar and 3D structures, SCCs can be mainly divided into two categories: metallacycles (e.g., rhomboidal, triangular, rectangular, and hexagonal) and metallacages (e.g., tetrahedral, hexahedral, and dodecahedral). The directional coordination bonds enable the efficient formation of metallacycles and metallacages with well-defined architectures and geometries. SCCs exhibit several advantages, including good directionality, strong interaction force, tunable modularity, and good solution processability, making them highly attractive for biomedical applications, especially in cellular imaging and cancer therapy. Compared with their molecular precursors, SCCs demonstrate enhanced cellular uptake and a strengthened tumor accumulation effect, owing to their inherently charged structures. These properties and the chemotherapeutic potential inherent to organic platinum complexes have promoted their widespread application in antitumor therapy. Furthermore, the defined structures of SCCs, achieved via the design modification of assembly elements and introduction of different functional groups, enable them to combat malignant tumors through multipronged treatment modalities. Because the development of cancer-treatment methodologies integrated in clinics has evolved from single-modality chemotherapy to synergistic multimodal therapy, the development of functional SCCs for synergistic cancer therapy is crucial. While some pioneering reviews have explored the bioapplications of SCCs, often categorized by a specific function or focusing on the specific metal or ligand types, a comprehensive exploration of their synergistic multifunctionality is a critical gap in the current literature.In this Account, we focus on platinum-based SCCs and their applications in cancer therapy. While other metals, such as Pd-, Rh-, Ru-, and Ir-based SCCs, have been explored for cancer therapy by Therrien and Casini et al., platinum-based SCCs have garnered significant interest, owing to their unique advantages in antitumor therapy. These platinum-based SCCs, which enhance antitumor efficacy, are considered prominent candidates for cancer therapies owing to their desirable properties, such as potent antitumor activity, exceptionally low systemic toxicity, active tumor-targeting ability, and enhanced cellular uptake. Furthermore, diverse diagnostic and therapeutic modalities (e.g., chemotherapy, photothermal therapy, and photodynamic therapy) can be integrated into a single platform based on platinum-based SCCs for cancer therapy. Consequently, herein, we summarize our recent research on platinum-based SCCs for synergistic cancer therapy with particular emphasis on the cooperative interplay between different therapeutic methods. In the Conclusions section, we present the key advancements achieved on the basis of our research findings and propose future directions that may significantly impact the field.

Schiff bases and their metal complexes to target and overcome (multidrug) resistance in cancer.

Overcoming multidrug resistance (MDR) is one of the major challenges in cancer therapy. In this respect, Schiff base-related compounds (bearing a R1R2CNR3 bond) gained high interest during the past decades. Schiff bases are considered privileged ligands for various reasons, including the easiness of their preparation and the possibility to form complexes with almost all transition metal ions. Schiff bases and their metal complexes exhibit many types of biological activities and are used for the treatment and diagnosis of various diseases. Until now, 13 Schiff bases have been investigated in clinical trials for cancer treatment and hypoxia imaging. This review represents the first collection of Schiff bases and their complexes which demonstrated MDR-reversal activity. The areas of drug resistance covered in this article involve: 1) Modulation of ABC transporter function, 2) Targeting lysosomal ABCB1 overexpression, 3) Circumvention of ABC transporter-mediated drug efflux by alternative routes of drug uptake, 4) Selective activity against MDR cancer models (collateral sensitivity), 5) Targeting GSH-detoxifying systems, 6) Overcoming apoptosis resistance by inducing necrosis and paraptosis, 7) Reactivation of mutated p53, 8) Restoration of sensitivity to DNA-damaging anticancer therapy, and 9) Overcoming drug resistance through modulation of the immune system. Through this approach, we would like to draw attention to Schiff bases and their metal complexes representing highly interesting anticancer drug candidates with the ability to overcome MDR.

Design, synthesis, anti-infective potency and mechanism study of novel Ru-based complexes containing substituted adamantane as antibacterial agents.

Infections caused by Staphylococcus aureus (S. aureus) are increasing difficult to treat because this pathogen is easily resistant to antibiotics. However, the development of novel antibacterial agents with high antimicrobial activity and low frequency of resistance remains a huge challenge. Here, building on the coupling strategy, an adamantane moiety was linked to the membrane-active Ru-based structure and then developed three novel metalloantibiotics: [Ru(bpy)2(L)](PF6)2 (Ru1) (bpy = 2,2-bipyridine, L = amantadine modified ligand), [Ru(dmb)2(L)](PF6)2 (Ru2) (dmb = 4,4'-dimethyl-2,2'-bipyridine) and [Ru(dpa)2(L)](PF6)2 (Ru3), (dpa = 2,2'-dipyridylamine). Notably, complex Ru1 was identified to be the best candidate agent, showing greater efficacy against S. aureus than most of clinical antibiotics and low resistance frequencies. Mechanism studies demonstrated that Ru1 could not only increase the permeability of bacterial cell membrane and then caused the leakage of bacterial contents, but also promoted the production of reactive oxygen species (ROS) in bacteria. Importantly, complex Ru1 inhibited the biofilm formation, exotoxin secretion and increased the potency of some clinical used antibiotics. In addition, Ru1 showed low toxic in vivo and excellent anti-infective efficacy in two animal infection model. Thus, Ru-based metalloantibiotic bearing adamantane moiety are promising antibacterial agents, providing a certain research basis for the future antibiotics research.

Exploring Aqueous Coordination Chemistry of Highly Lewis Acidic Metals with Emerging Isotopes for Nuclear Medicine.

ConspectusNuclear medicine harnesses radioisotopes for the diagnosis and treatment of disease. While the isotopes 99mTc and 111In have enabled the clinical diagnosis of millions of patients over the past 3 decades, more recent clinical translation of numerous 68Ga/177Lu-based radiopharmaceuticals for diagnostic imaging and therapy underscores the clinical utility of metal-based radiopharmaceuticals in mainstream cancer treatment. In addition to such established radionuclides, advancements in radioisotope production have enabled the production of radionuclides with a broad range of half-lives and emission properties of interest for nuclear medicine. Chemical means to form kinetically inert, in vivo-compatible species that can be modified with disease-targeting vectors is imperative. This presents a challenge for radiosiotopes of elements where the aqueous chemistry is still underdeveloped and poorly understood. Here, we discuss our efforts to date in exploring the aqueous, radioactive coordination chemistry of highly Lewis acidic metal ions and how our discoveries apply to the diagnosis and treatment of cancer in preclinical models of disease. The scope of this Account includes approaches to aqueous coordination of to-date understudied highly Lewis acidic metal ions with radioisotopes of emerging interest and the modulation of well-understood coordination environments of radio-coordination complexes to induce metal-catalyzed reactivity for separation and pro-drug applications.First, we discuss the development of seven-coordinate, small-cavity macrocyclic chelator platform mpatcn/picaga as an exemplary case study, which forms robust complexes with 44Sc/47Sc isotopes. Due to the high chemical hardness and pronounced Lewis acidity of the Sc3+ ion, the displacement of ternary ligand H2O by 18/natF- can be achieved to form an inert Sc-18/natF bond. Corresponding coordination complex natSc-18F is in vivo compatible and forms a theranostic tetrad with corresponding 44Sc/47Sc, 177Lu complexes all exhibiting homologous biodistribution profiles. Another exceptionally hard, highly Lewis acidic ion with underdeveloped aqueous chemistry and emerging interest in nuclear medicine is 45Ti4+. To develop de novo approaches to the mononuclear chelation of this ion under aqueous conditions, we employed a fragment-based bidentate ligand screening approach which identified two leads. The screen successfully predicted the formation of [45Ti][Ti(TREN-CAM)], a Ti-triscatechol complex that exhibits remarkable in vivo stability. Furthermore, the fragment-based screen also identified approaches that enabled solid-phase separation of Ti4+ and Sc3+ of interest in streamlining the isotope production of 45Ti and accessing new ways to separate 44Ti/44Sc for the development of a long-lived generator system. In addition to establishing the inert chelation of Ti4+ and Sc3+, we introduce controlled, metal-induced reactivity of corresponding coordination complexes on macroscopic and radiotracer scales. Metal-mediated autolytic amide bond cleavage (MMAAC) enables the temperature-dependent release of high-molar-activity, ready-to-inject radiopharmaceuticals; cleavage is selectively triggered by coordinated trivalent Lewis acid nat/68Ga3+ or Sc3+. Following the scope of reactivity and mechanistic studies, we validated MMAAC for the synthesis of high-molar-activity radiopharmaceuticals to image molecular targets with low expression and metal-mediated prodrug hydrolysis in vivo.This Account summarizes how developing the aqueous coordination chemistry and tuning the chemical reactivity of metal ions with high Lewis acidity at the macroscopic and tracer scales directly apply to the radiopharmaceutical synthesis with clinical potential.

The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.

Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu2+ to Cu1+ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu+2 → Cu+1 redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.

Recently Reported Biological Activities and Action Targets of Pt(II)- and Cu(II)-Based Complexes.

Most diseases that affect human beings across the world are now treated with drugs of organic origin. However, some of these are associated with side effects, toxicity, and resistance phenomena. For the treatment of many illnesses, the development of new molecules with pharmacological potential is now an urgent matter. The biological activities of metal complexes have been reported to have antitumor, antimicrobial, anti-inflammatory, anti-infective and antiparasitic effects, amongst others. Metal complexes are effective because they possess unique properties. For example, the complex entity possesses the effective biological activity, then the formation of coordination bonds between the metal ions and ligands is controlled, metal ions provide it with extraordinary mechanisms of action because of characteristics such as d-orbitals, oxidation states, and specific orientations; metal complexes also exhibit good stability and good physicochemical properties such as water solubility. Platinum is a transition metal widely used in the design of drugs with antineoplastic activities; however, platinum is associated with side effects which have made it necessary to search for, and design, novel complexes based on other metals. Copper is a biometal which is found in living systems; it is now used in the design of metal complexes with biological activities that have demonstrated antitumoral, antimicrobial and anti-inflammatory effects, amongst others. In this review, we consider the open horizons of Cu(II)- and Pt(II)-based complexes, new trends in their design, their synthesis, their biological activities and their targets of action.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

Systematic review on antibacterial photodynamic therapeutic effects of transition metals ruthenium and iridium complexes.

The prevalence of antibiotic-resistant pathogenic bacteria poses a significant threat to public health and ranks among the principal causes of morbidity and mortality worldwide. Antimicrobial photodynamic therapy is an emerging therapeutic technique that has excellent potential to embark upon antibiotic resistance problems. The efficacy of this therapy hinges on the careful selection of suitable photosensitizers (PSs). Transition metal complexes, such as Ruthenium (Ru) and Iridium (Ir), are highly suitable for use as PSs because of their surface plasmonic resonance, crystal structure, optical characteristics, and photonics. These metals belong to the platinum family and exhibit similar chemical behavior due to their partially filled d-shells. Ruthenium and Iridium-based complexes generate reactive oxygen species (ROS), which interact with proteins and DNA to induce cell death. As photodynamic therapeutic agents, these complexes have been widely studied for their efficacy against cancer cells, but their potential for antibacterial activity remains largely unexplored. Our study focuses on exploring the antibacterial photodynamic effect of Ruthenium and Iridium-based complexes against both Gram-positive and Gram-negative bacteria. We aim to provide a comprehensive overview of various types of research in this area, including the structures, synthesis methods, and antibacterial photodynamic applications of these complexes. Our findings will provide valuable insights into the design, development, and modification of PSs to enhance their photodynamic therapeutic effect on bacteria, along with a clear understanding of their mechanism of action.

A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells.

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 µM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents.

Erbium(III) complexes with fluoroquinolones: Structure and biological properties.

Four erbium(III) complexes with the fluoroquinolones enrofloxacin, levofloxacin, flumequine and sparfloxacin as ligands were synthesized and characterized by a wide range of physicochemical and spectroscopic techniques as well as single-crystal X-ray crystallography. The compounds were evaluated for their activity against the bacterial strains Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Xanthomonas campestris, which was higher than that of the corresponding free quinolones. The interaction mode of the complexes with calf-thymus DNA is via intercalation, as suggested by diverse studies such as UV-vis spectroscopy, DNA-viscosity measurements and competitive studies with ethidium bromide. Fluorescence emission spectroscopy revealed the high affinity of the complexes for bovine and human serum albumin and the determined binding constants suggested a tight and reversible binding of the compounds with both albumins.

Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)quinoline-based Ir(III)-PTA complexes in MDA-MB-231 cancer cells.

Metal complexes play a crucial role in photo-activated chemotherapy (PACT), which has recently been used to treat specific disorders. Triple-negative breast cancer has an enormously high rate of relapse due to the existence and survival of cancer stem cells (CSCs) characterized by increased amounts of glutathione (GSH). Hence, designing a phototoxic molecule is an enticing area of research to combat triple-negative breast cancer (TNBC) via GSH depletion and DNA photocleavage. Herein, we focus on the application of PTA and non-PTA Ir(III) complexes for phototoxicity in the absence and presence of GSH against MDA-MB-231 TNBC cells. Between these two complexes, [Cp*IrIII(DD)PTA]·2Cl (DDIRP) exhibited better phototoxicity (IC50 ∼ 2.80 ± 0.52 µM) compared to the non-PTA complex [Cp*IrIII(DD)Cl]·Cl (DDIR) against TNBC cells because of the high GSH resistance power of the complex DDIRP. The significant potency of the complex DDIRP under photo irradiation in both normoxia and hypoxia conditions can be attributed to selective transportation, high cellular permeability and uptake towards the nucleus, GSH depletion by GSH-GSSG conversion, the ability of strong DNA binding including intercalation, and oxidative stress. The strong affinity to serum albumin, which serves as a carrier protein, aids in the transport of the complex to its target site while preventing glutathione (GSH) deactivation. Consequently, the complex DDIRP was developed as a suitable phototoxic complex in selective cancer therapy, ruling over the usual chemotherapeutic drug cisplatin and the PDT drug Photofrin. The ability of ROS generation under hypoxic conditions delivers this complex as a hypoxia-efficient selective metallodrug for the treatment of TNBC.

Indole-based NNN donor Schiff base ligand and its complexes: Sonication-assisted synthesis, characterization, DNA binding, anti-cancer evaluation and in-vitro biological assay.

A novel indole based NNN donor Schiff base ligand and its Ni(II), Zn(II) and Cd(II) complexes have been synthesized using sonication-assisted method which is a highly efficient eco-friendly mechanism. The synthesized complexes have been characterized using elemental analysis, UV-Vis spectroscopy, mass spectrometry, FT-IR, and NMR and are optimized using DFT approach, which provided their theoretical framework. The stoichiometry between the ligand and the metal ions was also determined using Job's method. The thermogravimetric (TGA/DSC) analyses confirm the stability for all complexes at room temperature followed by thermal decomposition in different steps. DNA binding activities have been assessed by employing UV-visible and fluorescence spectra using the CT-DNA. The estimated intrinsic binding constant (Kb) for NiL, ZnL, and CdL complexes was 6.00 × 105, 5.58 × 105, and 4.7 × 105, respectively. In accordance with the Kb value, the quenching constant (Ksv) values of NiL, ZnL, and CdL are 5.59 × 105 M-1, 4.3 × 105 M-1, and 4.08 × 105 M-1 respectively. The anticancer properties have been assessed using MTT Assay. It has been found that the Ni(II) complex (NiL) is the most potent among the series with IC50 of 169 µg/mL. An in-vitro antioxidant experiment using DPPH was used to evaluate the synthesizedcomplexes' ability to scavenge free radicals. The findings indicated that the complexes exhibited notable antioxidant properties. The antioxidant property ZnL has been found to be the highest with an IC50 of 2.91 µg/mL and it follows the order is ZnL > NiL > CdL > L. Using the egg albumin denaturation technique, the anti-inflammatory property have been assessed, and the amount of protein denaturation inhibition has been computed. NiL has the highest % inhibition among the series studied. Comparatively, the metal complexes have been reported to exhibit higher biological activities than the prepared Schiff base ligand. The reason for the excellent biological properties observed in the metal complexes could be attributed to the incorporation of the electron-withdrawing CH3COO- during complexation. Molecular docking studies have been performed on the 2GYT protein and it has been found that the complexes have excellent binding affinity, with NiL having the lowest binding energy of -6.93 Kcal mol-1. The values suggested that NiL is more effective against HePG2 cancer cells, which is also in accordance with the MTT Assay results.

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response.

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

Mechanism of Action of Antitumor Au(I) N-Heterocyclic Carbene Complexes: A Computational Insight on the Targeting of TrxR Selenocysteine.

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.

Chemotherapeutic Activities of New η6-p-Cymene Ruthenium(II) and Osmium(II) Complexes with Chelating SS and Tridentate SNS Ligands.

A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3ai, 3aii, 3aiii, 3bii/4aiii, 4bi, 4bii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5bi, 5civ/6bi, 6ci, 6civ) in the forms [MII(cym)(L)Cl]PF6 and [MII(cym)(L)]PF6 (M = Ru or Os, cym = η6-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a "piano-stool" geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3aii, 5civ, 5bi, 4aiii, 6ci, 6civ, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3ai, 3aiii, 3bii, 4bi, 4bii, and 6bi, which were found not to be selective between normal and tumor cell lines. The IC50 value of the tridentate half-sandwich complex 5bi (86 ± 9 µM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 µM). The pincer (SNS) osmium complexes 6ci (36 ± 10 µM) and 6civ (40 ± 4 µM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5civ was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 µM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand's spatial coordination, the nature of the metal center, and the charge of the metal complex ions.

Design, Synthesis, and Anti-Cancer Evaluation of Novel Water-Soluble Copper(I) Complexes Bearing Terpyridine and PTA Ligands.

This study presents a simple and energy-efficient self-assembly LAG synthetic method for novel water-soluble copper(I) complexes [Cu(terpy)(PTA)][PF6] (1) and [Cu(terpy)(PTA)2][PF6] (2). They were characterized by FT-IR, 1H, and 31P{1H} NMR spectroscopy, elemental analysis, and single-crystal/powder X-ray diffraction (for 2). The X-ray analysis of compound 2 indicates a bidentate coordination mode of terpyridine to the metal center. Variable-temperature NMR tests indicate dynamic properties for terpyridine in the case of both compounds, as well as for the PTA ligands in the case of 2. Additionally, compounds 1 and 2 exhibit interesting cytotoxic activity, which was tested on normal human dermal fibroblasts (NHDFs), human lung carcinoma (A549), human breast adenocarcinoma (MCF-7), and human cervix carcinoma (HeLa) established cell lines. In comparison to the other tested compounds, complexes 1 and 2 seem to have significantly lower IC50 values against cancer cells (A549, HeLa, MCF-7), indicating their potential as prospective anticancer agents. Moreover, both compounds show no significant toxicity towards normal skin cells (NHDFs), suggesting a certain selectivity in their action on cancer cells. Cisplatin as a reference compound also exhibited considerable cytotoxicity against cancer cells but with a low level of selectivity, which could lead to unwanted effects on normal cells. Remarkably, compounds 1 and 2 exhibit up to 30 times the cytotoxic activity of cisplatin, with a six-fold lower toxicity to normal cells. They also interact strongly with human serum albumin, suggesting potential therapeutic applications. Overall, these compounds hold significant promise as potential chemotherapeutic agents.

Investigating the anticancer potential of 4-phenylthiazole derived Ru(II) and Os(II) metalacycles.

In this contribution we report the synthesis, characterization and in vitro anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by 1H-, 13C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed. Additionally, their stability and behaviour in aqueous solutions was determined by UV-Vis spectroscopy. Their cellular accumulation, their ability of inducing apoptosis, as well as their interference in the cell cycle were studied in SW480 colon cancer cells. The anticancer potencies were investigated in three human cancer cell lines and revealed IC50 values in the low micromolar range, in contrast to the biologically inactive ligands.

Mitochondria-targeted ruthenium(II) complexes for photodynamic therapy and GSH detection in living cells.

Photodynamic therapy is an emerging tumor therapy that kills tumor cells by activating reactive oxygen species (ROS) produced by photosensitizers. Mitochondria, as an important organelle, are the main generator of cellular ROS. Therefore, the development of photosensitizers capable of targeting mitochondria could significantly enhance the efficacy of photodynamic therapy. In this study, two novel ruthenium(II) complexes, Ru-1 and Ru-2, were designed and synthesized, both of which were functionalized with α,ß-unsaturated ketones for sensing of glutathione (GSH). The crystal structures of the two complexes were determined and they exhibited good recognition of GSH by off-on luminescence signals. The complex Ru-2 containing aromatic naphthalene can enter the cells and react with GSH to generate a strong luminescence signal that can be used to monitor intracellular GSH levels through imaging. Ru-2 also has an excellent mitochondrial localization ability with a Pearson's coefficient of 0.95, which demonstrates that it can efficiently target the mitochondria of tumor cells to enhance the effectiveness of photodynamic therapy as a photosensitizer.

Synthesis, anticancer activity, and molecular docking of half-sandwich iron(II) cyclopentadienyl complexes with maleimide and phosphine or phosphite ligands.

In these studies, we designed and investigated the potential anticancer activity of five iron(II) cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All complexes were characterized with spectroscopic analysis viz. NMR, FT-IR, ESI-MS, UV-Vis, fluorescence, XRD (for four complexes) and elemental analyses. For biological studies, we used three types of cells-normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and non-small-cell lung cancer A549 cells. We evaluated cell viability and DNA damage after cell incubation with these complexes. We observed that all iron(II) complexes were more cytotoxic for HL-60 cells than for A549 cells. The complex CpFe(CO)(P(OPh)3)(η1-N-maleimidato) 3b was the most cytotoxic with IC50 = 9.09 µM in HL-60 cells, IC50 = 19.16 µM in A549 and IC50 = 5.80 µM in PBM cells. The complex CpFe(CO)(P(Fu)3)(η1-N-maleimidato) 2b was cytotoxic only for both cancer cell lines, with IC50 = 10.03 µM in HL-60 cells and IC50 = 73.54 µM in A549 cells. We also found the genotoxic potential of the complex 2b in both types of cancer cells. However, the complex CpFe(CO)2(η1-N-maleimidato) 1 which we studied previously, was much more genotoxic than complex 2b, especially for A549 cells. The plasmid relaxation assay showed that iron(II) complexes do not induce strand breaks in fully paired ds-DNA. The DNA titration experiment showed no intercalation of complex 2b into DNA. Molecular docking revealed however that complexes CpFe(CO)(PPh3) (η1-N-maleimidato) 2a, 2b, 3b and CpFe(CO)(P(OiPr)3)(η1-N-maleimidato) 3c have the greatest potential to bind to mismatched DNA. Our studies demonstrated that the iron(II) complex 1 and 2b are the most interesting compounds in terms of selective cytotoxic action against cancer cells. However, the cellular mechanism of their anticancer activity requires further research.