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1.
Dalton Trans ; 51(4): 1489-1501, 2022 Jan 25.
Article in English | MEDLINE | ID: mdl-34989381

ABSTRACT

We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 µM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.


Subject(s)
Breast Neoplasms/drug therapy , Coordination Complexes/pharmacology , Lung Neoplasms/drug therapy , Ruthenium Compounds/pharmacology , Thiourea/analogs & derivatives , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/therapeutic use , Female , Humans , Ruthenium Compounds/chemical synthesis , Ruthenium Compounds/therapeutic use , Thiourea/chemistry
2.
Dalton Trans ; 51(4): 1333-1343, 2022 Jan 25.
Article in English | MEDLINE | ID: mdl-34989734

ABSTRACT

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.


Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/therapeutic use , Pyridines/therapeutic use , Ruthenium Compounds/therapeutic use , Animals , Antineoplastic Agents/chemistry , Apoptosis , Benzimidazoles , Calcium , Caspase 3/genetics , Caspase 3/metabolism , Caspase 9/genetics , Caspase 9/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , DNA Damage , Female , Gene Expression Regulation, Neoplastic/drug effects , Mice , Mice, Inbred BALB C , Mitochondrial Membranes/drug effects , Pyridines/chemistry , Reactive Oxygen Species , Ruthenium Compounds/chemistry , Xenograft Model Antitumor Assays
3.
J Pharmacol Exp Ther ; 380(1): 47-53, 2022 01.
Article in English | MEDLINE | ID: mdl-34728560

ABSTRACT

Ruthenium compounds, nitric oxide donors in biologic systems, have emerged as a promising therapeutic alternative to conventional drugs in anticancer chemotherapy and as a potential neuroprotective agent with fewer cytotoxic effects. This minireview summarizes promising studies with ruthenium complexes and their roles in cancer, neuroinflammation, neurovascular, and neurodegenerative diseases. The up-to-date evidence supports that ruthenium-based compounds have beneficial effects against gliomas and other types of brain cancers, reduce motor symptoms in models of cerebral ischemia-reperfusion, and may act in the control of nociceptive and inflammatory events, such as those seen in early Alzheimer's disease. More studies are needed to fill many current knowledge gaps about the intricate and complex biologic effects and therapeutic-related mechanisms of ruthenium, stimulating further research. SIGNIFICANCE STATEMENT: This minireview summarizes studies addressing the role of ruthenium compounds on neurological illnesses, focusing on brain cancer and neurovascular and neurodegenerative diseases. No such review is available in the literature.


Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Nitric Oxide Donors/therapeutic use , Ruthenium Compounds/therapeutic use , Animals , Brain Neoplasms/metabolism , Humans , Neurodegenerative Diseases/metabolism
4.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: mdl-34638791

ABSTRACT

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.


Subject(s)
Neoplasms/drug therapy , Ruthenium Compounds/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Cell Line, Tumor , Coordination Complexes , Drug Screening Assays, Antitumor , Female , Humans , Indoles/pharmacology , Indoles/therapeutic use , Ovarian Neoplasms/drug therapy , Pancreatic Neoplasms/drug therapy , Reactive Oxygen Species , Ruthenium Compounds/chemical synthesis , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use
5.
Toxicol Appl Pharmacol ; 426: 115618, 2021 09 01.
Article in English | MEDLINE | ID: mdl-34126112

ABSTRACT

WHO suggests that colon cancer incidences are rising steadily, propelling researchers to search for novel chemotherapeutic options. Metal-based chemotherapy is a potential forte to explore ruthenium-based complexes, exhibiting the capability to influence a variety of cellular targets. We discovered the chemotherapeutic effects of ruthenium-rifampicin complex on HT-29 and HCT-116 human colorectal cell lines and on a chemically developed murine colorectal cancer model. Complex was synthesized and characterized by analytical techniques and evaluation of antioxidant potential along with DNA binding capabilities. The complex minimizes cellular propagation and initiates apoptotic events in the colon cancer cell lines of HT-29 and HCT-116. The results of the in vivo study suggest that the complex has been successful in minimizing the wide spectrum of aberrant crypt foci and hyperplastic lesions, as well as encouraging elevated amounts of CAT, SOD and glutathione. Along with that, p53 could be modulated by the ruthenium-rifampicin complex to interfere with apoptosis in colon carcinoma, initiated by the intrinsic apoptotic trail facilitated through Bcl2 and Bax, thus controlling the Akt/mTOR/VEGF pathway coupled through the WNT/ß-catenin trail. Ruthenium-rifampicin chemotherapy could interrupt, retract or interrupt the progression of colorectal cancer through modifying intrinsic apoptosis including the antiangiogenic pathway, thereby achieving the function of a potential contender in chemotherapy in the near future.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Rifampin/therapeutic use , Ruthenium Compounds/therapeutic use , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Cycle/drug effects , Colon/drug effects , Colon/pathology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Combinations , Female , HCT116 Cells , HT29 Cells , Humans , Male , Mice, Inbred BALB C , Proto-Oncogene Proteins c-akt/metabolism , Rats, Wistar , Rifampin/pharmacology , Rifampin/toxicity , Ruthenium Compounds/pharmacology , Ruthenium Compounds/toxicity , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Tumor Microenvironment/drug effects , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factor A/metabolism
6.
Int J Mol Sci ; 22(9)2021 Apr 28.
Article in English | MEDLINE | ID: mdl-33924780

ABSTRACT

Procoagulant snake venoms have been inhibited by the ruthenium containing compounds CORM-2 and RuCl3 separately, presumably by interacting with critical histidine or other sulfur-containing amino acids on key venom enzymes. However, combinations of these and other platinoid containing compounds could potentially increase, decrease or not affect the procoagulant enzyme function of venom. Thus, the purpose of this investigation was to determine if formulations of platinoid compounds could inhibit venom procoagulant activity and if the formulated compounds interacted to enhance inhibition. Using a human plasma coagulation kinetic model to assess venom activity, six diverse venoms were exposed to various combinations and concentrations of CORM-2, CORM-3, RuCl3 and carboplatin (a platinum containing compound), with changes in venom activity determined with thrombelastography. The combinations of CORM-2 or CORM-3 with RuCl3 were found to enhance inhibition significantly, but not in all venoms nor to the same extent. In sharp contrast, carboplatin-antagonized CORM-2 mediated the inhibition of venom activity. These preliminary results support the concept that platinoid compounds may inhibit venom enzymatic activity at the same or different molecular sites and may antagonize inhibition at the same or different sites. Further investigation is warranted to determine if platinoid formulations may serve as potential antivenoms.


Subject(s)
Blood Coagulation/drug effects , Organometallic Compounds/therapeutic use , Ruthenium Compounds/therapeutic use , Snake Bites/drug therapy , Carboplatin/pharmacology , Carboplatin/therapeutic use , Drug Evaluation, Preclinical , Drug Therapy, Combination , Humans , Organometallic Compounds/pharmacology , Ruthenium Compounds/pharmacology , Snake Venoms/pharmacology , Thrombelastography
7.
ACS Appl Mater Interfaces ; 12(28): 31205-31216, 2020 Jul 15.
Article in English | MEDLINE | ID: mdl-32628016

ABSTRACT

Oxidative stress induced by reactive oxygen species (ROS) is one of the major pathological mechanisms of acute kidney injury (AKI). Inorganic nanomaterial-mediated antioxidant therapy is considered a promising method for the prevention of AKI; however, currently available antioxidants for AKI exhibit limited clinical efficacy due to the glomerular filtration threshold (∼6 nm). To address this issue, we developed ultrasmall RuO2 nanoparticles (RuO2NPs) (average size ≈ 2 nm). The NPs show excellent antioxidant activity and low biological toxicity. In addition, they can pass through the glomerulus to be excreted. These properties in combination make the ultrasmall RuO2NPs promising as a nanozyme for the prevention of AKI. The NP catalytic properties mimic the activity of catalase, peroxidase, superoxide dismutase, and glutathione peroxidase. The nanozyme can be efficiently and rapidly absorbed by human embryonic kidney cells while significantly reducing ROS-induced apoptosis by eliminating excess ROS. After intravenous injection, the ultrasmall RuO2NPs significantly inhibit the development of AKI in mice. In vivo toxicity experiments demonstrate the biosafety of the NPs after long-term preventing. The multienzyme-like activity and biocompatibility of the ultrasmall RuO2NPs makes them of great interest for applications in the fields of biomedicine and biocatalysis.


Subject(s)
Acute Kidney Injury/drug therapy , Ruthenium Compounds/chemistry , Animals , Catalase/metabolism , Catalysis , Glutathione Peroxidase/metabolism , Humans , Mice , Nanoparticles/chemistry , Oxidative Stress/drug effects , Peroxidase/metabolism , Reactive Oxygen Species/metabolism , Ruthenium Compounds/therapeutic use , Superoxide Dismutase/metabolism
8.
Mol Pharm ; 17(1): 145-154, 2020 01 06.
Article in English | MEDLINE | ID: mdl-31800255

ABSTRACT

Cryptococcus neoformans (C. neoformans) is one of the most well-known zoonotic fungal pathogens. Cryptococcal encephalitis remains a major cause of morbidity and mortality in immunocompromised hosts. Effective and targeting killing of C. neoformans in the brain is an essential approach to prevent and treat cryptococcal encephalitis. In this study, a fluorescent polypyridyl ruthenium complex RC-7, {[phen2Ru(bpy-dinonyl)](PF6)2 (phen = 1,10-phenanthroline, bpy-dinonyl = 4,4'-dinonyl-2,2'-bipyridine)}, was screened out, which showed a highly fungicidal effect on C. neoformans. The values of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) in antifungal activities were significantly lower than fluconazole as the control. Moreover, RC-7 was prepared as a brain-targeting nanoliposome (RDP-liposome; RDP is a peptide derived from rabies virus glycoprotein) for in vivo application. The results revealed that the liposomes could accumulate in the encephalitis brain and play an antifungal role. Compared with the cryptococcal encephalitis model mice, the RDP-liposomes remarkably prolonged the survival days of the encephalitis-bearing mice from 10 days to 24 days. Here, we introduce a polypyridyl ruthenium complex that could be used as a novel antifungal agent, and this study may have a broad impact on the development of targeted delivery based on ruthenium complex-loaded liposomes for theranostics of cryptococcal encephalitis.


Subject(s)
Antifungal Agents/administration & dosage , Brain/drug effects , Cryptococcosis/drug therapy , Cryptococcus neoformans/drug effects , Infectious Encephalitis/drug therapy , Liposomes/administration & dosage , Nanocapsules/administration & dosage , Ruthenium Compounds/administration & dosage , Animals , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/therapeutic use , Brain/microbiology , Brain/pathology , Cells, Cultured , Cryptococcosis/microbiology , Cryptococcosis/mortality , Cryptococcus neoformans/metabolism , Fluconazole/administration & dosage , Fluconazole/therapeutic use , Glycoproteins/chemistry , Infectious Encephalitis/microbiology , Infectious Encephalitis/mortality , Liposomes/chemical synthesis , Liposomes/chemistry , Liposomes/ultrastructure , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Microscopy, Electron, Transmission , Nanocapsules/chemistry , Nanocapsules/therapeutic use , Neurons/drug effects , Peptide Fragments/chemistry , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use , Theranostic Nanomedicine , Tissue Distribution , Viral Proteins/chemistry
9.
Life Sci ; 213: 57-65, 2018 Nov 15.
Article in English | MEDLINE | ID: mdl-30326218

ABSTRACT

AIMS: Ruthenium (II) complexes are promising anticancer molecules due its pharmacological properties and selectivity to cells tumor. The aim of this work was to study the cytotoxic activity, and apoptosis induction of two new ruthenium complexes on a human gastric cancer cell line. MAIN METHODS: Two ruthenium(II) complexes were synthesized: [(H2pbbzim)Ru(tpy-Ph-COOCH3)](Cl)2 (Ru-UCN1), and [(tpy)Ru(tpy-Ph-bzH)](Cl)2 (Ru-UCN3), and their anticancer capacity determined by cytotoxic assays, gene expression analysis, caspase activation and confocal microscopy. KEY FINDINGS: Ru-UCN3 is more notably cytotoxic than cisplatin in human gastric cancer cells AGS at 24 h, while Ru-UCN1 is more active against gastric cancer cells than cisplatin at 48 h. The complexes induce apoptosis as shown by RT-qPCR, protease activity, and confocal microscopy. Ru-UCN1 induces the overexpression of pro-apoptotic genes at 3 and 6 h, whereas Ru-UCN3 induces overexpression of these genes at 12 and 24 h. Ru-UCN1 treatment shows a strong activation of caspases 3/7 at 24 h, which was not observed for Ru-UCN3 treatment in the same timeframe. SIGNIFICANCE: Taken together, this data suggests that Ru-UCN1 and to a lesser extent, Ru-UCN3, may be interesting anticancer agents for gastric cancer.


Subject(s)
Ruthenium Compounds/pharmacology , Stomach Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor/drug effects , Cell Survival/drug effects , Cisplatin/pharmacology , Dose-Response Relationship, Drug , Humans , Ruthenium/pharmacology , Ruthenium/therapeutic use , Ruthenium Compounds/therapeutic use , Stomach Neoplasms/drug therapy , Structure-Activity Relationship
10.
J Biol Inorg Chem ; 23(3): 425-435, 2018 05.
Article in English | MEDLINE | ID: mdl-29569084

ABSTRACT

The new ruthenium (III) complex has been synthesized and characterized by elemental analysis, FT-IR, UV-Vis, EI-Mass, EPR spectroscopy, and magnetic susceptibility measurement. Cytotoxic effects of organoruthenium (II/III) complexes 1a, 1b, and 2a, and their ligands (TSC1 and TSC2) in cultured human ovarian (A2780, SKOV-3, and OVCAR-3) and colon (DLD, CCD18Co, and Caco-2) cells have been investigated comparing reactivity of the Ru (II/III) complexes and their free TSC ligands. The complexes exhibit higher cytotoxicity in three cancer cell lines than in normal cells. The binding with CT-DNA and BSA of the all complexes were weak compared with their ligand in spite of the cellular uptake of these complexes into the cytoplasm and then nucleus while their cytotoxic effects were vice versa. All the results showed that Complex 1b has more efficient cytotoxicity on the colon cancer cells than ovarian cancer cells. However, Complex 2a is a better drug candidate especially for antitumor therapy of metastasized ovarian cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Organometallic Compounds/chemistry , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use , Thiophenes/chemistry , Thiosemicarbazones/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Electron Spin Resonance Spectroscopy , Humans , Spectrum Analysis/methods
11.
Molecules ; 23(2)2018 Feb 22.
Article in English | MEDLINE | ID: mdl-29470443

ABSTRACT

The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1-5 µM) dependent inhibitory effect on platelet aggregation induced by collagen (1 µg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 µM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca2+]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases.


Subject(s)
Blood Platelets/drug effects , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation/drug effects , Ruthenium Compounds/chemistry , Collagen/chemistry , Humans , Phosphorylation , Platelet Activation/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/therapeutic use , Ruthenium/chemistry , Ruthenium Compounds/chemical synthesis , Ruthenium Compounds/therapeutic use , Structure-Activity Relationship , Thrombosis/drug therapy
12.
Met Ions Life Sci ; 182018 02 05.
Article in English | MEDLINE | ID: mdl-29394025

ABSTRACT

There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Design , Neoplasms/drug therapy , Organometallic Compounds/therapeutic use , Ruthenium Compounds/therapeutic use , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Coordination Complexes , Humans , Models, Molecular , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Organometallic Compounds/adverse effects , Organometallic Compounds/chemistry , Organometallic Compounds/metabolism , Protein Binding , Ruthenium Compounds/adverse effects , Ruthenium Compounds/chemistry , Ruthenium Compounds/metabolism , Structure-Activity Relationship
13.
J Med Chem ; 60(3): 899-912, 2017 02 09.
Article in English | MEDLINE | ID: mdl-28075589

ABSTRACT

Three water-soluble Ru(II) chiral heteroleptic coordination compounds [Ru(en)(pdto)]Cl2 (1), [Ru(gly)(pdto)]Cl (2), and [Ru(acac)(pdto)]Cl (3), where pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, have been synthezised and fully characterized. The crystal structures of compounds 1-3 are described. The IC50 values for compounds 1-3 are within nanomolar range (14, 12, and 6 nM, respectively). The cytotoxicity for human peripheral blood lymphocytes is extremely low (>100 µM). Selectivity indexes for Ru(II) compounds are in the range 700-1300. Trophozoites exposed to Ru(II) compounds die through an apoptotic pathway triggered by ROS production. The orally administration to infected mice induces a total elimination of the parasite charge in mice faeces 1-2-fold faster than metronidazole. Besides, all compounds inhibit the trophozoite proliferation in amoebic liver abscess induced in hamster. All our results lead us to propose these compounds as promising candidates as antiparasitic agents.


Subject(s)
Antiprotozoal Agents/pharmacology , Entamoeba histolytica/drug effects , Ruthenium Compounds/pharmacology , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/therapeutic use , Apoptosis/drug effects , Cells, Cultured , Cricetinae , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Liver Abscess, Amebic/drug therapy , Mice , Reactive Oxygen Species/metabolism , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use , Stereoisomerism
14.
J Inorg Biochem ; 157: 62-72, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26828285

ABSTRACT

Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(DQTT)](ClO4)2 (1) (DQTT=12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(DQTT)](ClO4)2 (2) (bpy=2,2'-bipyridine), [Ru(phen)2(DQTT)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(DQTT)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized by elemental analysis, ESI-MS, (1)H NMR and (13)C NMR. The cytotoxic activity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method. The IC50 values of complexes 1-4 against BEL-7402 cells are 31.8 ± 1.0, 35.8 ± 1.6, 29.0 ± 0.8 and 25.0 ± 0.9 µM, respectively. The morphological apoptosis was investigated with AO/EB (acridine orange/ethidium bromide) and Hoechst 33258 staining methods. The DNA damage was assayed by comet assay. The inhibition of cell migration was evaluated by the wound healing assay. The levels of ROS (reactive oxygen species) and the changes of mitochondrial membrane potential were studied under fluorescent microscope. The percentages in the cells of apoptotic and necrotic cells and the cell cycle arrest were determined by flow cytometry. The expression of Bcl-2 family proteins was investigated by western blot analysis. The results show that the complexes induce BEL-7402 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulation of the expression of Bcl-2 family proteins.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use , Antineoplastic Agents/pharmacology , Cell Line , Comet Assay , DNA Damage/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Reactive Oxygen Species/metabolism , Ruthenium Compounds/pharmacology , Wound Healing/drug effects
15.
Chem Commun (Camb) ; 52(13): 2705-8, 2016 Feb 14.
Article in English | MEDLINE | ID: mdl-26756042

ABSTRACT

Appending anthracene units to [(bpy)2Ru(dpp)](2+) results in Ru(II) agents that exhibit dynamic photoreactivity towards DNA and protein. [(Anthbpy)(bpy)Ru(dpp)](2+) and [(Anthbpy)2Ru(dpp)](2+) are the first metal-organic Ru(II) agent with dpp ligands shown to photomodify DNA in the presence or absence of oxygen, while also binding protein in an oxygen-dependent manner.


Subject(s)
Photochemotherapy , Photosensitizing Agents/chemistry , Ruthenium Compounds/chemistry , Photosensitizing Agents/therapeutic use , Ruthenium Compounds/therapeutic use
16.
Med Hypotheses ; 80(6): 841-6, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23587478

ABSTRACT

Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site. Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes.


Subject(s)
Drug Delivery Systems/methods , Macromolecular Substances/therapeutic use , Models, Biological , Neoplasms/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Ruthenium Compounds/therapeutic use , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cyclic GMP/metabolism , Humans , Macromolecular Substances/metabolism , Phosphodiesterase Inhibitors/metabolism , Ruthenium Compounds/metabolism , Transferrin/metabolism
17.
Dalton Trans ; 40(31): 7817-23, 2011 Aug 21.
Article in English | MEDLINE | ID: mdl-21629963

ABSTRACT

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Drug Design , Neoplasms/drug therapy , Organometallic Compounds/chemistry , Ruthenium Compounds/therapeutic use , Animals , Dimethyl Sulfoxide/analogs & derivatives , Dimethyl Sulfoxide/pharmacokinetics , Drug Delivery Systems , Humans , Indazoles/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Organometallic Compounds/therapeutic use , Ruthenium Compounds/chemistry , Ruthenium Compounds/pharmacokinetics
18.
Curr Med Chem ; 17(31): 3701-38, 2010.
Article in English | MEDLINE | ID: mdl-20846109

ABSTRACT

Low molecular weight and high molecular weight metal ion binders present in blood plasma are shortly described. The binding of vanadium and ruthenium complexes by these components has received much attention, namely their interactions with human serum albumin and transferrin, and these studies are critically reviewed. The influence of the protein binding on the bioavailability of the prospective drugs, namely on the transport by blood plasma and uptake by cells is also discussed. It is concluded that vanadium compounds are mainly transported in blood by transferrin, but that no study has properly addressed the influence of albumin and transferrin in the vanadium uptake by cells. Ruthenium complexes bind strongly to HSA, most likely at the level of His residues, leading to the formation of stable adducts. If the kinetics of binding to this protein is fast enough, probably they are mainly transported by this serum protein. Nevertheless, at least for a few Ru(III)-complexes, hTf seems to play an active role in the uptake of ruthenium, while HSA may provide selectivity and higher activity for the compounds due to an enhanced permeability effect.


Subject(s)
Blood Proteins/metabolism , Coordination Complexes/blood , Ruthenium Compounds/blood , Vanadium Compounds/blood , Biological Transport , Clinical Trials as Topic , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coordination Complexes/therapeutic use , Humans , Molecular Weight , Protein Binding , Ruthenium/blood , Ruthenium/chemistry , Ruthenium/metabolism , Ruthenium Compounds/chemistry , Ruthenium Compounds/metabolism , Ruthenium Compounds/therapeutic use , Ruthenium Radioisotopes/blood , Ruthenium Radioisotopes/chemistry , Ruthenium Radioisotopes/metabolism , Ruthenium Radioisotopes/therapeutic use , Serum Albumin/metabolism , Spectrum Analysis , Transferrin/metabolism , Vanadium/blood , Vanadium/chemistry , Vanadium/metabolism , Vanadium Compounds/chemistry , Vanadium Compounds/metabolism , Vanadium Compounds/therapeutic use
19.
Cancer Chemother Pharmacol ; 66(1): 1-9, 2010 May.
Article in English | MEDLINE | ID: mdl-20213076

ABSTRACT

Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and antimetastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.


Subject(s)
Antineoplastic Agents , Dimethyl Sulfoxide/analogs & derivatives , Indazoles , Neoplasm Metastasis/drug therapy , Organometallic Compounds , Ruthenium Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Dimethyl Sulfoxide/chemistry , Dimethyl Sulfoxide/pharmacology , Dimethyl Sulfoxide/therapeutic use , Drug Screening Assays, Antitumor , Drugs, Investigational/pharmacology , Humans , Indazoles/chemistry , Indazoles/pharmacology , Indazoles/therapeutic use , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Organometallic Compounds/therapeutic use , Ruthenium Compounds/chemistry , Ruthenium Compounds/therapeutic use
20.
Biol Trace Elem Res ; 135(1-3): 98-111, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19727575

ABSTRACT

The aim of present study was to verify the in vitro antitumor activity of a ruthenium complex, cis-(dichloro)tetraammineruthenium(III) chloride (cis-[RuCl(2)(NH(3))(4)]Cl) toward different tumor cell lines. The antitumor studies showed that ruthenium(III) complex presents a relevant cytotoxic activity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) cell lines and a very low cytotoxicity toward human peripheral blood mononuclear cells. The ruthenium(III) complex decreased the fraction of tumor cells in G0/G1 and/or G2-M phases, indicating that this compound may act on resting/early entering G0/G1 cells and/or precycling G2-M cells. The cytotoxic activity of a high concentration (2 mg mL(-1)) of cis-[RuCl(2)(NH(3))(4)]Cl toward Jurkat cells correlated with an increased number of annexin V-positive cells and also the presence of DNA fragmentation, suggesting that this compound induces apoptosis in tumor cells. The development of new antineoplastic medications demands adequate knowledge in order to avoid inefficient or toxic treatments. Thus, a mechanistic understanding of how metal complexes achieve their activities is crucial to their clinical success and to the rational design of new compounds with improved potency.


Subject(s)
Antineoplastic Agents/therapeutic use , Ruthenium Compounds/therapeutic use , Animals , Breast Neoplasms/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cytotoxicity, Immunologic/drug effects , Female , Humans , Jurkat Cells/drug effects , Lymphoma, B-Cell/drug therapy , Mice , Ruthenium/therapeutic use , Sarcoma 180/drug therapy
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