A Novel Substituted Benzo[]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent.

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(CN)(phen)], -, containing a π-expansive cyclometalating substituted benzo[]quinoxaline ligand (CN ligand) (phen = 1,10-phenanthroline). Compounds - in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex in most sensitive HCT116 cells. accumulates in the cellular membranes.

Multiaction Pt(IV) Prodrugs Releasing Cisplatin and Dasatinib Are Potent Anticancer and Anti-Invasive Agents Displaying Synergism between the Two Drugs.

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically.

Photoactivatable, mitochondria targeting dppz iridium(III) complex selectively interacts and damages mitochondrial DNA in cancer cells.

Cyclometalated Ir(III) complex [Ir(L)(dppz)]PF (where L = 1-methyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole and dppz = dipyrido [3,2-a:2',3'-c]phenazine) (Ir1) is potent anticancer agent whose potency can be significantly increased by irradiation with blue light. Structural features of the cyclometalated Ir(III) complex Ir1 investigated in this work, particularly the presence of dppz ligand possessing an extended planar area, suggest that this complex could interact with DNA. Here, we have shown that Ir1 accumulates predominantly in mitochondria of cancer cells where effectively and selectively binds mitochondrial (mt)DNA.

Novel 2-(5-Arylthiophen-2-yl)-benzoazole Cyclometalated Iridium(III) dppz Complexes Exhibit Selective Phototoxicity in Cancer Cells by Lysosomal Damage and Oncosis.

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)(dppz)], -, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was -CFCH or -MeNCH. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives ( and ) were the best performers, being also activatable with green or red light.

N-Indolyl diiron vinyliminium complexes exhibit antiproliferative effects in cancer cells associated with disruption of mitochondrial homeostasis, ROS scavenging, and antioxidant activity.

The indole scaffold has been established as a key organic moiety for developing new drugs; on the other hand, a range of diiron bis-cyclopentadienyl complexes have recently emerged for their promising anticancer potential. Here, we report the synthesis of novel diiron complexes with an indole-functionalized vinyliminium ligand (2-5) and an indole-lacking analogue for comparative purposes (6), which were characterized by analytical and spectroscopic techniques. Complexes 2-6 are substantially stable in DMSO‑d and DMEM-d solutions at 37 °C (8% average degradation after 48 h) and display a balanced hydrophilic/lipophilic behaviour (LogP values in the range -0.

Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death.

A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC ; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions.

Ir(III) Compounds Containing a Terdentate Ligand Are Potent Inhibitors of Proliferation and Effective Antimetastatic Agents in Aggressive Triple-Negative Breast Cancer Cells.

Herein, we report a series of new octahedral iridium(III) complexes - of the type [Ir(N^N^N)(C^N)Cl]PF (N^N^N = 4'-(-tolyl)-2,2':6',2″-terpyridine; C^N = deprotonated 2-arylbenzimidazole backbone) to introduce new metal-based compounds for effective inhibition of metastatic processes in triple-negative breast cancer (TNBC). The results show that the structural modifications within the C^N scaffold strongly impact the antimetastatic properties of these complexes in TNBC cells. Furthermore, testing the antimetastatic effects of the investigated Ir complexes revealed that the highest antimetastatic activity in TNBC cells is exhibited by complex .

Cyclometalated Benzimidazole Osmium(II) Complexes with Antiproliferative Activity in Cancer Cells Disrupt Calcium Homeostasis.

We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-:2',3'-]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation.

Ruthenium(II)-Tris-pyrazolylmethane Complexes Inhibit Cancer Cell Growth by Disrupting Mitochondrial Calcium Homeostasis.

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes - in 77-99% yields. Products were fully structurally characterized.

Is antitumor Pt(IV) complex containing two axial lonidamine ligands a true dual- or multi-action prodrug?

This work studied the mechanism of action of a Pt(IV) complex 2 bearing two axial lonidamine ligands, which are selective inhibitors of aerobic glycolysis. The presence of two lonidamine ligands in 2 compared to the parent Pt(II) complex increased its antiproliferative activity, cellular accumulation, and changed its cell cycle profile and mechanism of cell death. In 3D cell culture, 2 showed exceptional antiproliferative activity with IC50 values as low as 1.

Gallium(III) Complex with Cloxyquin Ligands Induces Ferroptosis in Cancer Cells and Is a Potent Agent against Both Differentiated and Tumorigenic Cancer Stem Rhabdomyosarcoma Cells.

In this work, gallium(III) complex with cloxyquin (5-chloro-8-quinolinol, HClQ) ligands is shown to effectively inhibit proliferation of rhabdomyosarcoma cells, the frequent, aggressive, and poorly treatable cancer of children. It offers striking selectivity to cancer cells compared to noncancerous human fibroblasts. The data reveal that the complex induces ferroptosis in rhabdomyosarcoma cells, likely due to interfering with iron metabolism.

Dipyridophenazine iridium(III) complex as a phototoxic cancer stem cell selective, mitochondria targeting agent.

In this work, the mechanism underlying the anticancer activity of a photoactivatable Ir(III) compound of the type [Ir(C^N)(dppz)][PF] where C^N = 1-methyl-2-(2'-thienyl)benzimidazole (complex 1) was investigated. Complex 1 photoactivated by visible light shows potent activity against highly aggressive and poorly treatable Rhabdomyosarcoma (RD) cells, the most frequent soft tissue sarcomas of children. This remarkable activity of 1 was observed not only in RD cells cultured in 2D monolayers but, more importantly, also in 3D spheroids, which resemble in many aspects solid tumors and serve as a promising model to mimic the in vivo situation.

Novel cis-Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action.

One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation.

Metallohelix vectors for efficient gene delivery via cationic DNA nanoparticles.

The design of efficient and safe gene delivery vehicles remains a major challenge for the application of gene therapy. Of the many reported gene delivery systems, metal complexes with high affinity for nucleic acids are emerging as an attractive option. We have discovered that certain metallohelices-optically pure, self-assembling triple-stranded arrays of fully encapsulated Fe-act as nonviral DNA delivery vectors capable of mediating efficient gene transfection.

A [Pt(cis-1,3-diaminocycloalkane)Cl] analog exhibits hallmarks typical of immunogenic cell death inducers in model cancer cells.

The platinum drugs belong to prevailing chemotherapeutics used in the treatment of cancer. At present, however, the search for new anticancer metal-based drugs that operate by the mechanisms distinct from those of the conventional chemotherapeutics is very active. Furthermore, it has been demonstrated that cytotoxic chemotherapy and immunotherapy may exert a highly synergistic anticancer activity.

Induction of immunogenic cell death in cancer cells by a photoactivated platinum(IV) prodrug.

The platinum() prodrug trans,trans,trans-[Pt(N)(OH)(py)] (1) is stable and non-toxic in the dark, but potently cytotoxic to cancer cells when irradiated by visible light, including cisplatin-resistant cells. On irradiation with visible light, it generates reactive Pt(II) species which can attack DNA, and produces reactive oxygen species (ROS) and reactive nitrogen species (RNS) which exert unusual effects on biochemical pathways. We now show that its novel mechanism of action includes induction of immunogenic cell death (ICD).

A Cyclometalated Ir Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells.

A cyclometalated Ir complex conjugated to a far-red-emitting coumarin, Ir -COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis.

Platinum(IV)-Estramustine Multiaction Prodrugs Are Effective Antiproliferative Agents against Prostate Cancer Cells.

Herein, we describe the synthesis, characterization, and biological properties of Pt(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of "multiaction" Pt(IV) prodrugs.

Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo.

Monosaccharides are added to the hydrophilic face of a self-assembled asymmetric Fe metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water-stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53 ) with respect to the non-cancerous ARPE-19 cell line. While the most selective compound is a glucose-appended enantiomer, its cellular entry is not mainly glucose transporter-mediated.

Optically Pure Metallohelices That Accumulate in Cell Nuclei, Condense/Aggregate DNA, and Inhibit Activities of DNA Processing Enzymes.

The water-compatible optically pure metallohelices made by self-assembly of simple nonpeptidic organic components around Fe(II) ions are now recognized as a distinct subclass of helicates that exhibit similar architecture to some natural cationic antimicrobial peptides. Notably, a new series of metallohelices was recently shown to exhibit biological activity, displaying high, structure-dependent activity against bacteria. It is also important that, thanks to their properties, such metallohelices can exhibit specific interactions with biomacromolecules.

Platinum (IV) Derivatives with Cinnamate Axial Ligands as Potent Agents Against Both Differentiated and Tumorigenic Cancer Stem Rhabdomyosarcoma Cells.

To design an anticancer drug capable of inhibiting not only the proliferation of the differentiated tumor cells but also reducing the tumorigenic capability of cancer stem cells (CSCs), the new Pt prodrugs with axial cinnamate ligands were synthesized. We demonstrate their superior antiproliferative activity in monolayer and 3D spheroid antiproliferative activity tests using panel of cancer cell lines. An outstanding activity was found against rhabdomyosarcoma cells, one of the most problematic and poorly treatable pediatric tumors.

An anticancer Os(II) bathophenanthroline complex as a human breast cancer stem cell-selective, mammosphere potent agent that kills cells by necroptosis.

Conventional chemotherapy is mostly effective in the treatment of rapidly-dividing differentiated tumor cells but has limited application toward eliminating cancer stem cell (CSC) population. The presence of a very small number of CSCs may contribute to the development of therapeutic resistance, metastases, and relapse. Thus, treatment failure by developing novel anticancer drugs capable of effective targeting of CSCs is at present a major challenge for research focused on chemotherapy of cancer.

A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton.

The substitution inert platinum agent [Pt(1 S,2 S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far.

Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated Ir Complex Conjugated to a Far-Red Emitting Coumarin.

Although cyclometalated Ir complexes have emerged as promising photosensitizers for photodynamic therapy, some key drawbacks still hamper clinical translation, such as operability in the phototherapeutic window and reactive oxygen species (ROS) production efficiency and selectivity. In this work, a cyclometalated Ir complex conjugated to a far-red-emitting coumarin, Ir -COUPY, is reported with highly favourable properties for cancer phototherapy. Ir -COUPY was efficiently taken up by HeLa cells and showed no dark cytotoxicity and impressive photocytotoxicity indexes after irradiation with green and blue light, even under hypoxia.

Correction: Simultaneous delivery of olaparib and carboplatin in PEGylated liposomes imparts this drug combination hypersensitivity and selectivity for breast tumor cells.

[This corrects the article DOI: 10.18632/oncotarget.25466.