Journal of Inorganic Biochemistry

Ionic mononuclear [Fe] and heterodinuclear [Fe,Ru] bis(diphenylphosphino)alkane complexes: Synthesis, spectroscopy, DFT structures, cytotoxicity, and biomolecular interactions

Iron(II) and Ru(II) half-sandwich compounds encompass some promising pre-clinical anticancer agents whose efficacy may be tuned by structural modification of the coordinated ligands. Here, we combine two such bioactive metal centres in cationic bis(diphenylphosphino)alkane-bridged heterodinuclear [Fe

Dinuclear copper(II) complexes with a bridging bis(chalcone) ligand reveal considerable in vitro cytotoxicity on human cancer cells and enhanced selectivity

A bis(chalcone) molecule (H

The mechanism of copper transporters in ovarian cancer cells and the prospect of cuproptosis

Copper transporters can not only carry copper (Cu) to maintain the homeostasis of Cu in cells but also transport platinum-based chemotherapy drugs. The effect of copper transporters on chemosensitivity has been demonstrated in a variety of malignancies. In addition, recent studies have reported that copper transporters can act as vectors to induce cuproptosis. Therefore, copper transporters can act on cells through different mechanisms to achieve different purposes. This review mainly describes the current research progress of the intracellular transport mechanism of copper transporters and cuproptosis, and prospects for the application of them in the treatment of ovarian cancer (OC).

An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism

PhenolaTi is a promising Ti(IV) anticancer complex, with high stability and cytotoxicity, without notable toxic side-effects. Its cellular mechanism was proposed to relate to ER stress. Herein, we investigated the downstream effects of this mode of action in two cancer cell lines: ovarian carcinoma A2780 and cervical adenocarcinoma HeLa. First, although Ti(IV) is a non-redox metal, the formation of mitochondrial reactive oxygen species (ROS) was detected with live-cell imaging. Then, we inspected the effect of the mitochondrial ROS on cytotoxicity, using two methods: (a) addition of compounds that either elevate or reduce the mitochondrial glutathione concentration, thus affecting the oxidative state of the cells; and (b) scavenging mitochondrial ROS. Unlike the results observed for cisplatin, neither method influenced the cytotoxicity of phenolaTi, implying that ROS formation was a mere side effect of its activity. Additionally, live cell imaging displayed the hypoxia induced by phenolaTi, which can be associated with ROS formation. Overall, the results support the notion that ER-stress is the main cellular mechanism of phenolaTi, leading to hypoxia and mitochondrial ROS. The distinct mechanism of phenolaTi, which is different from that of cisplatin, combined with its stability and favorable anticancer properties, altogether make it a strong chemotherapeutic drug candidate.

Cytotoxicity and DNA interaction in a series of aryl terminated iminopyridine Pt(II) complexes

A series of iminopyridine complexes of platinum(II), bearing a flexible diethereal, aryl terminated residue, where the size of aryl group is varied from phenyl to 9-anthracenyl, was synthesized. The new complexes are soluble and stable in DMSO/H

Zn(II) and Co(II) derivatives anchored with scorpionate precursor: Antiproliferative evaluation in human cancer cell lines

A 'scorpionate' type precursor [bdtbpza = bis(3,5-di-t-butylpyrazol-1-yl)acetate] has been employed to synthesize two mononuclear Zn

DNA interaction of a fluorescent, cytotoxic pyridinimino platinum(II) complex

New pyridinimino complexes of platinum(II) [PtCl

On the path to gold: Monoanionic Au bisdithiolate complexes with antimicrobial and antitumor activities

The emergence of resistance to antimicrobial and anticancer drugs poses severe threats to public health worldwide, highlighting the need for more efficient treatments. Here, four monoanionic Au bisdithiolate complexes [Au(mnt)

Ru complexes containing Cp, mPTA and natural purine bases (mPTA = methyl-N-1,3,5-triaza-7-phosphaadamantane): Evaluation of their antiproliferative activity, solubility and redox properties

Complexes [RuCp(Adeninate-κN9)(mPTA)

Ruthenium(II) polypyridyl complexes with benzothiophene and benzimidazole derivatives: Synthesis, antitumor activity, solution studies and biospeciation

With the aim to incorporate pharmacophore motifs into the Ru(II)-polypyridyl framework, compounds [Ru(II)(1,10-phenantroline)

Insights into the transformation of VO2+ motif to VO3+, V2O34+ and VO2+ motifs and their interconversion along with a detailed mechanistic study of their anti-cancer activity in SiHa cervical cancer cells

The basic criteria for the formation of complexes with VO

Ruthenium(II)-mercapto complexes induce cell damage via apoptosis pathway on ovarian cancer cells

Ovarian cancer represents a leading cause of cancer-related deaths in women worldwide. Chemotherapeutic agents are usually employed to treat the patients, and Ruthenium(II)-based compounds have been investigated as possible substitutes for platinum drugs. In this work, we studied three different Ru(II)-phosphine-mercapto complexes (1-3) as potential cytotoxic agents against A2780 and A2780-cisR ovarian cancer cells. A time-dependent cytotoxicity was observed for 2, which also exhibited better selectivity than cisplatin control. A similar cytotoxic behavior was observed on 3D tumor spheroids. Although no changes were observed in cell cycle distribution, compound 2 affected the mitochondrial membrane potential on A2780 cells, and caused cell death via apoptotic pathway, which was confirmed by flow cytometry assay. Western blotting experiments revealed that 2 affected the expression of p53, PCNA, γH2AX and cleaved caspase-3, making it a promising anticancer agent for ovarian cancer.

Oxaliplatin bioconjugates with human ferritin obtained by protein surface decoration: Characterization and biological evaluation

Human H-type ferritin is an attractive protein candidate for the targeted delivery of anticancer metallodrugs. In this study, we report on the formation of ferritin conjugates with oxaliplatin via a direct reaction in solution. This process typically results in the decoration of the protein surface with metallofragments of the type ((R,R)-trans-1,2-diaminocyclohexane)platinum(II) (DACH)Pt. A series of oxaliplatin/ferritin conjugates were obtained and systematically characterized by ESI-MS and ICP measurements. The ESI-MS profiles obtained demonstrate that adduct formation is both time- and concentration-dependent. The nature, stoichiometry and likely anchoring sites of the ferritin-bound platinum fragments were elucidated by ESI-MS analysis coupled with trypsinization experiments. We then evaluated the biological effects of the oxaliplatin-ferritin cage bioconjugate (preprared at 120:1 metal to protein ratio) in comparison to the free drug on A2780 human ovarian cancer cells. We observed that conjugation of oxaliplatin to ferritin resulted in similar platinum uptake by the cells compared to the free drug. However, the anticancer activity of the drug was unexpectedly lost. We critically discuss the implications of these results for the design and preparation of new anticancer platinum-ferritin bioconjugates.

A Pt(II) complex bearing N-heterocycle ring induced ferroptotic cell death in ovarian cancer

Cisplatin is a widely used chemotherapeutic agent which interacts with DNA to form Pt-DNA adducts, leading to DNA double-strand breaks and apoptosis. Resistance is the major obstacle in the clinical application of cisplatin. A quinoline derivative based Pt(II) complex PtQ was synthesized and characterized. As an analogue of cisplatin, PtQ demonstrated a novel anticancer mechanism in ovarian cancer. PtQ caused excessive production of reactive oxygen species (ROS), which triggered ferroptotic cell death in ovarian cancer. Cystine/glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4) which alleviate lipid peroxidation were both downregulated in PtQ-treated SKOV3 cells. Furthermore, PtQ induced DNA single-strand breaks and suppressed the expression of single-strand breaks repair protein PARP1. Mechanism studies demonstrated that PtQ can hopefully bypass the signaling pathways mediated cisplatin resistance in ovarian cancer.

Antitumor active trans‑platinum complexes through metabolic stability and enhanced cellular accumulation

Utilizing isoquinoline as a carrier ligand, we have evaluated the reactivity of selected trans‑platinum planar amine (TPA) carboxylate compounds by varying the leaving carboxylate group (acetate, hydroxyacetate, and lactate) in an effort to optimize the cytotoxic and metabolic efficiency. To measure the pharmacological properties of these compounds, a combination of systematic biophysical and biological studies were carried out mainly involving substitution reaction with NAM (N-acetyl-methionine), effects on DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects. TPA compounds showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum, while displaying a distinct micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle. Monitoring the TPA compounds with NAM suggests the following trend for the reactivity: hydroxyacetate > lactate > acetate. The same trend was seen for the cytotoxicity in tumor cells and DNA binding, while the rate of drug inactivation/protein binding in cells was not significantly different among these leaving groups. Thus, our results show superior cellular efficacy of TPA compounds and distinct micromolar cytotoxic activities different than cisplatin. Moreover, we found the TPA compounds had prolonged survival and decreased tumor burden compared to the control mice in a relevant human ovarian cancer mouse model with A2780 cells expressing luciferase. Therefore, we propose that further optimization of the basic TPA structure can give further enhanced in vivo activity and may eventually be translated into the development of clinically relevant non-traditional platinum drugs.

Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents

It is a major challenge to design novel multifunctional metal-based chemotherapeutic agents for anti-tumor and anti-metastasis applications. Two complexes (OA-Ir and OA-Ru) were synthesized via CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction from nontoxic Ir-N

Trinuclear ruthenium(II) polypyridyl complexes: Evaluation as photosensitizers for enhanced cervical cancer treatment

Trinuclear ruthenium(II) polypyridyl complexes anchored to benzimidazole-triazine / trisamine scaffolds were investigated as photosensitizers for photodynamic therapy. The trinuclear complexes were noted to produce a significant amount of singlet oxygen in both DMF and aqueous media, are photostable and show appreciable emission quantum yields (ɸ

Metal (Au, Pt, Pd, Ni) Bis(dithiolene) complexes as dual-action agents combating cancer and trypanosomatid infections

Cancer and infection diseases pose severe threats to public health worldwide stressing the need for more effective and efficient treatments. Thus, the search for broad-spectrum activity drugs seems justifiable and urgent. Herein, we investigate the anticancer and antitrypanosomatid (anti-Trypanosoma cruzi) activities of eight monoanionic metal bis(dithiolene) complexes, [Ph

Thermoresponsive carboplatin-releasing prodrugs

Platinum-based anticancer drugs, while potent, are associated with numerous and severe side effects. Hyperthermia therapy is an effective adjuvant in anticancer treatment, however, clinically used platinum drugs have not been optimised for combination with hyperthermia. The derivatisation of existing anticancer drugs with appropriately chosen thermoresponsive moieties results in drugs being activated only at the heated site. Perfluorinated chains of varying lengths were installed on carboplatin, a clinically approved drug, leading to the successful synthesis of a series of mono- and di- substituted platinum(IV) carboplatin prodrugs. Some of these complexes display relevant thermosensitivity on ovarian cancer cell lines, i.e., being inactive at 37 °C while having comparable activity to carboplatin under mild hyperthermia (42 °C). Nuclear magnetic resonance spectroscopy and mass spectrometry indicated that carboplatin is likely the active platinum(II) anticancer agent upon reduction and cyclic voltammetry revealed that the length of the fluorinated alkyl chain has a strong influence on the rate of carboplatin formation, regulating the subsequent cytotoxicity.

Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties

The antiproliferative properties of a series of structurally-related gold(I) and silver(I) linear complexes inspired to the clinically established gold-based drug auranofin were investigated in A2780 ovarian cancer cells and in their auranofin (A2780/AF-R) and cisplatin (A2780/CDDP-R) resistant counterparts. In A2780 cells and in the cisplatin-resistant subline, gold-based analogues manifested a cytotoxicity profile comparable or superior to auranofin, while the silver-based analogues were less active; both gold and silver complexes overcame cisplatin resistance. Yet, a high degree of cross resistance toward gold analogues was noticed in A2780/AF-R cells. In the same cell line cross-resistance for silver analogues was also observed, though lower. All metal complexes were scrutinized for their ability to inhibit thioredoxin reductase (TrxR), the putative primary target for auranofin: overall, gold compounds were more potent TrxR inhibitors than the corresponding silver compounds, probably, as the consequence of the stronger binding of gold to the active site selenocysteine residue. These results highlight that the thiosugar ligand of auranofin is not essential for cytotoxicity while the nature of the metal center (gold/silver) plays a relevant role in its modulation. In addition, a rather clear correlation was found between cytotoxic potency of tested compounds and their ability to inhibit TrxR activity, being gold compounds more effective than silver analogues. However, the residual TrxR activity, measured in A2780 cells treated with the half-maximal inhibitory concentrations of various metal complexes, resulted far higher than expected. These results suggest that additional cytotoxic mechanisms must be operative. The implications of these results are discussed.

A prodrug of 3-(ferrocenylaminocarbonyloxymethyl)phenol activated by reactive oxygen species in cancer cells

Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.

Novel triorganotin complexes based on phosphonic acid ligands: Syntheses, structures and in vitro cytostatic activity

Six novel organotin phosphonate complexes, [(Me

Mechanisms associated with cuproptosis and implications for ovarian cancer

Ovarian cancer, a profoundly fatal gynecologic neoplasm, exerts a substantial economic strain on nations globally. The formidable challenge of its frequent relapse necessitates the exploration of novel cytotoxic agents, efficacious antineoplastic medications with minimal adverse effects, and strategies to surmount resistance to primary chemotherapeutic agents. These endeavors aim to supplement extant pharmacological interventions and elucidate molecular mechanisms underlying induced cytotoxicity, distinct from conventional therapeutic modalities. Recent scientific research has unveiled a novel form of cellular demise, known as copper-death, which is contingent upon the intracellular concentration of copper. Diverging from conventional mechanisms of cellular demise, copper-death exhibits a pronounced reliance on mitochondrial respiration, particularly the tricarboxylic acid (TCA) cycle. Tumor cells manifest distinctive metabolic profiles and elevated copper levels in comparison to their normal counterparts. The advent of copper-death presents alluring possibilities for targeted therapeutic interventions within the realm of cancer treatment. Hence, the primary objective of this review is to present an overview of the proteins and intricate mechanisms associated with copper-induced cell death, while providing a comprehensive summary of the knowledge acquired regarding potential therapeutic approaches for ovarian cancer. These findings will serve as valuable references to facilitate the advancement of customized therapeutic interventions for ovarian cancer.

8-hydroxyquinoline-N-oxide copper(II)- and zinc(II)-phenanthroline and bipyridine coordination compounds: Design, synthesis, structures, and antitumor evaluation

RETRACTED: New Cu(II) coordination polymer inhibits cervical cancer development by regulating BRCA1 protein via miR-9-5p

A novel Cu(II)-based coordination polymer [chemical composition, {[CuL(CH