Also published as: Sabatella M, Pioli M, Maji M, Juszczak M, Vinoda Rani M, Mariadason, J M, Gallardo M, Böhme M, Kasprzak M, Alfiean M, Zalibera M, Mitrović M, Bartholomä M, Yue M, Ren M, Osmak M, Tian M, Jakubaszek M, Brook M, Gouveia M, Aldrovandi M, Dénes M, Woldeselassie M, Harlos M, Schaier M, Klajner M, Qian M, Schlame M, Albanell-Fernández M, Harkiolaki M, Lucas M, Nomura M, Zeng M, Acharya M, Dickerson M, Hektoen, M, Walczyk M, Muralisankar M, Lekka M, Font-Bardia M, Ionta M, Nieddu M, Nabissi M, Palaniandavar M, Sztiller-Sikorska M, Porchia M, Zheng M, Ranjani M, Aatif A M, Abinaya M, Feelisch M, Devocelle M, Assfalg M, Zienkiewicz-Machnik M, Cecchini M, Subramani M, Lari M, Zoldakova M, Mozzicafreddo M, Milczarek M, Olivar-Villanueva M, Hernaez M, Sá M, Rothemund M, Vilaseca M, Feizi-Dehnayebi M, Ouyang M, Liu M, Bortoluzzi M, Piccioli M, Dürst M, Kostić M, Sedić M, Káplár M, Ahn M, Contel M, Vraneš M, Holtgrewe M, Lv M, Delibašić M, Vaquero M, Dow M, Patra M, Kou M, Lo Bello M, Bian M, Shen M, Dalla Pozza M, Li M, Fogagnolo M, Bosch M, Bazett M, Hadiji M, Muir M, Qin M, Meyer M, Chorilli M, Panigati M, Singh M, Kerou M, Grazul M, Schmid M, Zhang M, Conrad M, Shaloski M, Concepción Gimeno M, Lanznaster M, Međedović M, Xie M, Gao M, Dulović M, Haghdoost M, Miñana M, Hirahara M, Capdevila M, Sanaú M, Létourneau M, Chikuma M, Martínez-Estévez M, Matiková-Mal'arová M, Magrane M, Abovsky M, Rojo de la Vega M, Caraglia M, Sattler M, Folgueira M, Shukla M, Dontenwill M, Camacho-Artacho M, Verma M, Lesser, M, El Sibai M, Sarkar M, Peruzzini M, Chen M, Zou M, Kokoschka M, Martins M, Kandawa-Shultz M, Rusz M, Lange M, Yu M, Markuliak M, Dodds M, Reithofer M, Chesi M, Xiangjun M, Nechay M, Kotlyar M, Helena Garcia M, Guelfi M, Berecka M, Milovanović M, Shee M, Gladkikh M, Savic M, Khater M, Seldin M, Wills M, Myint M, Živanović M, Korb M, Abid M, Zhou M, Feuermann M, Taghizadeh Shool M, Koester M, Bruno, Peter M, Guevara M, Planas M, Block M, Mastore M, Papadakis M, Pellegrino M, Tancredi M, Cocchietto M, Mohanraj M, Zain Aldin M, Arif M, Guerrero M, Aleksandrova M, Borsari M, Huang M, Malček M, Kaplanis M, Zhong M, Lapins M, Park M, Rúbio, Guilherme M D M, Vojtek M, Gazvoda M, Girek M, Piccolo M, Kubanik M, Tharaud M, Shao M, Pan M, Azam M, Nakai M, Pruess M, Siegler M, Piškor M, Jordà-Redondo M, Knopp M, Qasim Warraich M, Bicho M, Mauro M, Ohtsuji M, Piccolella M, Korkmaz M, Yang M, Tang M, Khawar Rauf M, Massi M, Paravatou-Petsotas M, Preiner M, Kaiser M, Karpiel M, Danyel M, Lavaud M, Koronkiewicz M, Sidhoum M, Hanif M, Brabender M, Fernandez M, Peretz M, Matera M, Lin M, Matković M, Łomzik M, Zhao M, Cohen M, Groessl M, Pozzato M, Corsini M, Dobroschke M, Bubrin M, Haukka M, P M, Hammad M, Wagner M, Grätzel M, Raftari M, Lehvaslaiho M, Spehr M, Micksche M, Falasca M, Hannink M, Grigalunas M, Sameni M, Velusamy M, Oleszak M, Carcelli M, Momcilovic M, Kosanić M, Trichet M, Duan M, Trifuoggi M, Gelbcke M, Salamini-Montemurri M, Novak M, de Souza Oliveira M, Xia M, Sun M, He M, Mohanty M, Lutz M, Hejl M, Juhas M, Kim M, Navarro M, Pfeffer M, Więckowska-Szakiel M, Salome M, Krenn M, Melchart M, Yamamoto M, Pongratz M, Jovanović M, Koukouvitaki M, Brown, Lewis M, Fan M, Spink M, Hollenstein M, Chhabra M, Abul Farah M, Zeller M, Ali M, Salmain M, Buczkowska M, Nikhil M, Tourte M, Digman M, Bacac M, Babin M, Paulpandi M, Hu M, Rincón M, Clémancey M, Crestani M, Skreta M, Nieger M, Alagesan M, López Torres M, Scarpi-Luttenauer M, Albrecht M, Murali M, Lesiów M, Dotou M, Pavlović M, Negi M, Dharmasivam M, Richert M, Wühr M, Azmanova M, González-Bártulos M, Angeletti M, Milenković M, Soudani M, Fandzloch M, Cargile M, Sajid Ali M, Tampere M, Casals M, Ganeshpandian M, Pernar M, Hetu M, Machuqueiro M, Lepoivre M, Soula M, Yao M, Iglesias M, Marloye M, Hooshmand M, Tuohan M, M M, Skocic M, Butinar M, Erby M, Riisom M, Monari M, Ibarrola-Villava M, Tanić M, Pizurica M, Chakrabarti M, Koch M, Grujović M, Đorđić Crnogorac M, Scaccaglia M, Wang M, Goldberg M, Audano M, Orts-Arroyo M, Zegke M, Nieminen M, Galanski M, Bette M, Monsalve M, Martínez M, Storch M, Cieslak M, Frik M, El-Sibai M, Ferrer M, Redrado M, Musthafa M, Płotek M, Pérez-Manrique M, Rossi M, Ravi M, Schmidlehner M, Pinto M, Dodson M, Goicuría M, Martínez-Alonso M, Eknæs, M, Řezáčová M, Cuccioloni M
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In th Show more
Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)2dppz](ClO4)2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer. Show less
Following the identification of a ruthenium(II)-arene complex with an ethacrynic acid-modified imidazole ligand, which inhibits glutathione transferase (GST) and is cytotoxic to chemo-resistant cancer Show more
Following the identification of a ruthenium(II)-arene complex with an ethacrynic acid-modified imidazole ligand, which inhibits glutathione transferase (GST) and is cytotoxic to chemo-resistant cancer cells, a series of structurally related ruthenium(II)- and osmium(II)-p-cymene compounds have been prepared. In these complexes the ethacrynic acid is linked to the metals via appropriately modified pyridine ligands. The influence of the metal center and the metal:ethacrynic acid ratio on the cytotoxicity of the compounds was evaluated with the derivatives with one metal center and two ethacrynic acid moieties being the most potent against chemo-resistant A2780cisR cells (human ovarian cancer cells with acquired resistance to cisplatin). Moreover, compared to a complex with an ethacrynic acid-modified imidazole ligand (RAIMID-EA, Figure 2), these complexes display a significant degree of cancer cell specificity. Show less
An iridium (III) complex [Ir(ppy)2(BDPIP)]PF6 (Ir-1) was reported to show high anticancer activity and may be used as a potent anticancer drug. In the current study, we designed Show more
An iridium (III) complex [Ir(ppy)2(BDPIP)]PF6 (Ir-1) was reported to show high anticancer activity and may be used as a potent anticancer drug. In the current study, we designed and synthesized a novel iridium (III) complex and evaluated its potential inhibitory effect on the cancer cell growth in vitro and in vivo. This complex was found to display high cytotoxic activity in vitro and in vivo against A549 cell with a low IC50 value of 3.6 ± 0.3 μM and inhibiting percentage of tumor growth is 63.84% compared with the control. The complex also exhibited potencies superior to that of cisplatin toward A549 cell in vitro and in vivo. Further studies revealed that the complex can induce apoptosis and autophagy, enhance the ROS level, cause a decrease in the mitochondrial membrane potential and inhibit the cell invasion. Our findings indicated that the complex induced apoptosis in A549 through mitochondria dysfunction and PI3K/AKT/mTOR signaling pathways. Show less
Six cyclometalated iridium(iii) complexes bearing different numbers of fluorine atoms were synthesized. These complexes demonstrated much better anti-proliferation activities towards five tumour cell Show more
Six cyclometalated iridium(iii) complexes bearing different numbers of fluorine atoms were synthesized. These complexes demonstrated much better anti-proliferation activities towards five tumour cell lines than the widely used clinical chemotherapeutic agent cisplatin. Moreover, the anti-proliferation activities were correlated to the number of substituted fluorine atoms. Colocalization and inductively coupled plasma-mass spectrometry (ICP-MS) indicated that this series of complexes could penetrate cell membranes rapidly and preferentially target mitochondria. Manifesting high selectivity between tumour cells and normal cells and remarkable sensitivity to a cisplatin-resistant cell line (A549R), complex Ir6 was successfully developed as a novel anticancer agent (with IC50 values of 0.5 ± 0.1 μM for HeLa, 1.1 ± 0.2 μM for HepG2, 1.5 ± 0.3 μM for BEL-7402, 0.8 ± 0.1 μM for A549, and 0.7 ± 0.2 μM for A549R cell lines). Further mechanism studies including mitochondrial membrane potential depolarization and caspase 3/7 activation revealed that Ir6 induced apoptosis via mitochondrial pathways. These results demonstrated that complex Ir6 might be a promising candidate as a mitochondria-targeted theranostic anticancer agent. Show less
Seven novel half-sandwich IrIII cyclopentadienyl complexes, [(η5-Cpx)Ir(N^N)Cl]PF6, have been prepared and characterized, where Cpx is Cp* or the Show more
Seven novel half-sandwich IrIII cyclopentadienyl complexes, [(η5-Cpx)Ir(N^N)Cl]PF6, have been prepared and characterized, where Cpx is Cp* or the biphenyl derivative Cpxbiph (C5Me4C6H4C6H5), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cpxbiph complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NAD+via hydride transfer. Cpxbiph complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G2/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity. Show less
Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^C)Cl]PF6, where Cpx is pentamethylcyclopent Show more
Half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^C)Cl]PF6, where Cpx is pentamethylcyclopentadienyl (Cp*), or its phenyl (Cpxph = C5Me4C6H5) or biphenyl (Cpxbiph = C5Me4C6H4C6H5) derivatives, and the C^C-chelating ligands are different N-heterocyclic carbene (NHC) ligands, have been synthesized and characterized. Three X-ray crystal structures have been determined. Except for Cp* complex 1A, the other eleven complexes 1B-4C all showed potent cytotoxicity, with IC50 values ranging from 2.9 to 46.3 μM toward HeLa human cervical cancer cells. The potency toward HeLa cells increased with additional phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*, and increased with the size of chain substitution on the C^C-ligand in the order: ph > butyl > ethyl > methyl. Complex [(η5-C5Me4C6H4C6H5)Ir(L4)Cl]PF6 (4C) displayed the highest potency, and was about 3 times more active than the clinical platinum drug cisplatin. Complexes 1A-4C all undergo hydrolysis and their kinetics was studied. DNA binding appears not to be the major mechanism of action. The ability of these iridium complexes to catalyze hydride transfer from the coenzyme NADH to NAD+ was studied. Complexes [(η5-C5Me4C6H4C6H5)Ir(L2)Cl]PF6 (2C) and [(η5-C5Me4C6H4C6H5)Ir(L3)Cl]PF6 (3C) cause cell apoptosis and arrest the cell cycle at the G1 phase and G2/M phase when HeLa cancer cells are treated with different IC50 concentrations of the complexes, and increase the amount of reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs. Show less
Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, reveal Show more
Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties. Show less
Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene syntha Show more
Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene synthase, an enzyme involved in cholesterol synthesis. Show less
IID (Integrated Interactions Database) is the first database providing tissue-specific protein-protein interactions (PPIs) for model organisms and human. IID covers six species (S. cerevisiae (yeast), Show more
IID (Integrated Interactions Database) is the first database providing tissue-specific protein-protein interactions (PPIs) for model organisms and human. IID covers six species (S. cerevisiae (yeast), C. elegans (worm), D. melonogaster (fly), R. norvegicus (rat), M. musculus (mouse) and H. sapiens (human)) and up to 30 tissues per species. Users query IID by providing a set of proteins or PPIs from any of these organisms, and specifying species and tissues where IID should search for interactions. If query proteins are not from the selected species, IID enables searches across species and tissues automatically by using their orthologs; for example, retrieving interactions in a given tissue, conserved in human and mouse. Interaction data in IID comprises three types of PPI networks: experimentally detected PPIs from major databases, orthologous PPIs and high-confidence computationally predicted PPIs. Interactions are assigned to tissues where their proteins pairs or encoding genes are expressed. IID is a major replacement of the I2D interaction database, with larger PPI networks (a total of 1,566,043 PPIs among 68,831 proteins), tissue annotations for interactions, and new query, analysis and data visualization capabilities. IID is available at http://ophid.utoronto.ca/iid. Show less
Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand break Show more
Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3β (GSK3β) is a constitutively active kinase known to promote cell death. Here we show that phosphorylation of GSK3β on Ser(389) by p38 MAPK (mitogen-activated protein kinase) is induced selectively by DSBs through ATM (ataxia telangiectasia mutated) as a unique mechanism to attenuate the activity of nuclear GSK3β and promote survival of cells undergoing DSBs. Inability to inactivate GSK3β through Ser(389) phosphorylation in Ser(389)Ala knockin mice causes a decrease in the fitness of cells undergoing V(D)J recombination and CSR. Preselection-Tcrβ repertoire is impaired and antigen-specific IgG antibody responses following immunization are blunted in Ser(389)GSK3β knockin mice. Thus, GSK3β emerges as an important modulator of the adaptive immune response. Show less
A novel three components approach for the synthesis of bioactive Ru-arene pyridinylmethylene complexes has been developed using pyridine carboxaldehyde, amino pyridine and dichloro (p-cymene) rutheniu Show more
A novel three components approach for the synthesis of bioactive Ru-arene pyridinylmethylene complexes has been developed using pyridine carboxaldehyde, amino pyridine and dichloro (p-cymene) ruthenium(II) dimer as starting materials. These scaffolds were screened for their anticancer activity against breast cancer (MCF7) and human Epitheloid Cervix Carcinoma (HeLa) cell line. It was established that compounds [(η(6)-pcymene)RuCl(κ(2)-N,N-(3,5-dinitro-pyridin-2-yl)-pyridin-2-ylmethylene-amine)]PF6 (4o), [(η(6)-pcymene)RuCl(κ(2)-N,N-N-(3,5-dibromo-pyridin-2-yl)-pyridin-2-ylmethylene-amine)]PF6 (4c), [(η(6)-pcymene)RuCl(κ(2)-N,N-(3,5-dibromo-6-methylpyridin-2-yl)-pyridin-2-ylmethylene-amine)]PF6 (4j) and [(η(6)-pcymene)RuCl(κ(2)-N,N-3(3-bromo-5-methyl-pyridin-2-yl)-pyridin-2-ylmethylene-amine)]PF6 (4b) were significantly active against both the cell lines. Show less
Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistanc Show more
Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays. Show less
Three new ruthenium(II) complexes with hydrazone ligands, furan-2-carboxylic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(1)), furan-2-carboxylic acid [4-(ethyl-propyl-amino)-2-hydroxy-benzylidene]- Show more
Three new ruthenium(II) complexes with hydrazone ligands, furan-2-carboxylic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(1)), furan-2-carboxylic acid [4-(ethyl-propyl-amino)-2-hydroxy-benzylidene]-hydrazide (HL(2)) and furan-2-carboxylic acid (3-ethoxy-2-hydroxy-benzylidene)-hydrazide (HL(3)) were synthesized and characterized by various spectro-analytical techniques. The hydrazone ligands act as a tridendate ligand with ONO as the donor sites and are preferably found in the enol form in all the complexes. The molecular structure of the ligands was determined by single crystal X-ray diffraction technique. The interaction of the ligands and the complexes with CT-DNA were evaluated by an absorption titration method which revealed that the compounds interact with CT-DNA through intercalation. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the calf thymus DNA hydrolytically. Antioxidant studies showed that the ruthenium(II) complexes have a strong radical-scavenging properties. Further, the cytotoxic effect of the compounds examined on cancerous cell lines showed that the complexes exhibited substantial anticancer activity. Show less
We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest Show more
We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest for the synthesis of compounds with potential catalytic and medicinal applications. The general synthetic strategy has been applied in the preparation of novel cationic heterobimetallic ruthenium(ii)-gold(i) complexes that are highly cytotoxic to renal cancer Caki-1 and colon cancer HCT 116 cell lines while showing a synergistic effect and being more selective than their monometallic counterparts. Show less
In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, N Show more
In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, N-N is a bidentate chelating ligand (1,2-diaminoethane (en, 1), 1,2-diaminocyclohexane (dach, 2) or 2,2'-bipyridine (bpy, 3)). All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that all compounds are relatively labile leading to the formation of the corresponding aqua species 1aq-3aq. Their DNA binding ability was evaluated by UV-Vis spectroscopy, fluorescence quenching measurements and viscosity measurements. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (Ksv=1.1-2.7×104M-1). These experiments show that the ruthenium complexes interact with DNA via intercalation. The complexes bind to serum protein albumin displaying relatively high binding constants (Ksv=104-105M-1). Compound 3 displayed from high to moderate cytotoxicity against two cancer cell lines HeLa and A549 (with IC50ca. 12.7μM and 53.8μM, respectively), while complexes 1 and 2 showed only moderate cytotoxicity (with IC50ca. 84.8μM and 96.3μM, respectively) against HeLa cells. The cell cycle analysis (by flow cytometry) of HeLa and A549 cells treated with complex 3 shows minor changes on the cell cycle phase distribution. Show less
Couples of N-heterocyclic carbene complexes of ruthenium, iridium, platinum, and gold, each differing only in the carbene ligand being either 1,3-dimethylimidazol-2-ylidene (IM) or 1,3-dimethyl-N-boc- Show more
Couples of N-heterocyclic carbene complexes of ruthenium, iridium, platinum, and gold, each differing only in the carbene ligand being either 1,3-dimethylimidazol-2-ylidene (IM) or 1,3-dimethyl-N-boc-O-methylhistidin-2-ylidene (HIS), were assessed for their antiproliferative effect on seven cancer cell lines, their interaction with DNA, their cell cycle interference, and their vascular disrupting properties. In MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays only the platinum complexes were cytotoxic at single-digit micromolar IC50 concentrations with the (HIS)Pt complex being on average twice as active as the (IM)Pt complex. The former was highly efficacious against cisplatin-resistant HT-29 colon carcinoma cells where the latter had no effect. Both Pt complexes were accumulated by cancer cells and bound to double-helical DNA equally well. Only the (HIS)Pt complex modified the electrophoretic mobility of circular DNA in vitro due to the HIS ligand causing greater morphological changes to the DNA. Both platinum complexes induced accumulation of 518A2 melanoma cells in G2/M and S phase of the cell cycle. A disruption of blood vessels in the chorioallantoic membrane of fertilized chicken eggs was observed for both platinum complexes and the (IM)gold complex. The (HIS)platinum complex was as active as cisplatin in tumor xenografted mice while being tolerated better. We found that the HIS ligand may augment the cytotoxicity of certain antitumoral metal fragments in two ways: by acting as a transmembrane carrier increasing the cellular accumulation of the complex, and by initiating a pronounced distortion and unwinding of DNA. We identified a new (HIS)platinum complex which was highly cytotoxic against cancer cells including cisplatin-resistant ones. Show less
A ruthenium(II) complex [Ru(p-cymene)(NHC)Cl2] (NHC=1,3-bis(4-(tert-butyl)benzylimidazol-2-ylidene), referred to as L-4, has been designed and synthesized recently in order to look for new anticancer Show more
A ruthenium(II) complex [Ru(p-cymene)(NHC)Cl2] (NHC=1,3-bis(4-(tert-butyl)benzylimidazol-2-ylidene), referred to as L-4, has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. The anticancer activity and mechanism of action of L-4 in human esophageal squamous carcinoma EC109 cells were systematically investigated. The results revealed that L-4 exerted strong inhibitory effect on the proliferation of EC109 cells, and it arrested EC109 cells at G2/M phase, accompanied with the up-regulation of p53 and p21 and the down-regulation of cyclin D1. The results also showed that the reactive oxygen species (ROS)-dependent apoptosis of EC109 can be induced by L-4 via inhibiting the activity of glutathione reductase (GR), decreasing the ratio of glutathione to oxidized glutathione (GSH/GSSG), and leading to the generation of reactive oxygen species. The mitochondria-mediated apoptosis of EC109 induced by L-4 was also observed from the increase of Bax/Bcl-2 ratio, overload of Ca(2+), disruption of mitochondrial membrane potential (MMP), redistribution of cytochrome c, and activation of caspase-3/-9. However, the effects of L-4 on the cell viability, GR activity, GSH/GSSG ratio, reactive oxygen species level, mitochondria dysfunction and apoptosis induction were remarkably attenuated by adding the reactive oxygen species scavenger, NAC. Therefore, it was concluded that L-4 can inhibit the proliferation of EC109 cells via blocking cell cycle progression and inducing reactive oxygen species-dependent and mitochondria-mediated apoptosis. These findings suggested that the ruthenium(II) complex might be a potential effective chemotherapeutic agent for human esophageal squamous carcinoma (ESCC) and worthy of further investigation. Show less
To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy)2(C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity Show more
To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy)2(C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity assays with two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines. It is suggested that the complexes act as intercalators and/or DNA minor groove binders. Moreover, the complexes display favorable cytotoxicity activities with L1210 and HeLa, which in all cases were significantly more favorable than cisplatin. In contrast, the complexes exhibit appreciably lower cytotoxicity toward BALB/3T3 clone A31. Show less
Three ruthenium complexes [RuCl(CTZ)(bipy)(P-P)]PF6 [P-P=1,2-bis(diphenylphosphino)ethane (dppe-1), 1,4-bis(diphenylphosphino)butane (dppb-2) and 1,1'-bis(diphenylphosphino)ferrocene (dppf- Show more
Three ruthenium complexes [RuCl(CTZ)(bipy)(P-P)]PF6 [P-P=1,2-bis(diphenylphosphino)ethane (dppe-1), 1,4-bis(diphenylphosphino)butane (dppb-2) and 1,1'-bis(diphenylphosphino)ferrocene (dppf-3), bipy=2,2'-bipiridine and clotrimazole (CTZ) 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole] were synthesized. These complexes were characterized by a combination of elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, 1H, 13C{1H} and 31P{1H} nuclear magnetic resonance techniques, cyclic voltammetry and mass spectroscopy. Bovine serum albumin binding constants, which were in the range of 1.30-36.00×104M-1, and thermodynamic parameters suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. DNA interactions studied by spectroscopic titration, viscosity measurements, gel electrophoresis, circular dichroism, ethidium bromide displacement and reactions with guanosine and guanosine monophosphate indicated the DNA binding affinity primarily through non-covalent interactions. All complexes 1-3 were tested against the human carcinoma cell lines MCF-7 (breast), A549 (lung) and DU-145 (prostate) presenting promising IC50 values, between 0.50 and 14.00μM, in some cases lower than the IC50 for the reference drug (cisplatin). The antimicrobial activity assays of the complexes provided evidence that they are potential agents against mycobacterial infections, specifically against Mycobacterium tuberculosis H37Rv. Show less
Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) a Show more
Herein we report the synthesis, anticancer potency in vitro, biomolecule interaction, and preliminary mode of action studies of a series of cyclometalated 1,2,3-triazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) organometallics of the general form [(η6-p-cym)RuCl(κ2-C^N-L)] with varying substituents in postion 1 of the 1,2,3-triazole moiety. These cyclometalates were characterized by standard analytical methods and their structures unambiguously assigned by single crystal X-ray crystallography. The anticancer activity of these novel compounds was tested in the human tumor cell lines A549 (non-small cell lung cancer), SW480 (colon adenocarcinoma), and CH1/PA-1 (ovarian teratocarcinoma), and preliminary structure-activity relationships were derived from the obtained data sets. Various representatives exhibit promising antineoplastic effects with IC50 values down to the low micromolar range. The compounds readily formed stable DMSO adducts after aquation in DMSO-containing solution, but employing DMSO as solubilizer in cytotoxicity assays had no pronounced effect on the cytotoxicity, compared to analogous experiments with DMF for most compounds. We isolated and characterized selected DMSO adducts as triflate salts and found that they show activities in the same range as the parent chlorido metalacycles in MTT assays with the use of DMSO. Osmium(II) cyclometalates exhibited higher antiproliferative activities than their ruthenium(II) counterparts. The IC50 values within each metal series decreased with increasing lipophilicity, which was attributed to higher cellular accumulation. Investigations on their mode of action revealed that the prepared organometallics were unable to inhibit topoisomerase IIα. Still, the most cytotoxic representatives 2b and 3b showed pronounced effects on cell cycle distribution. Show less
The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4 Show more
The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC50 (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC50 are halved. Therefore, after replacing OH curcumin groups with OCH3, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity. Show less
This study performed in vitro and in vivo biological assays of the ruthenium (II) compound ct-[RuCl(CO)(dppb)(bipy)]PF6 (where, dppb=1,4-bis(diphenylphosphine)butane and bipy=2,2'-bipyridin Show more
This study performed in vitro and in vivo biological assays of the ruthenium (II) compound ct-[RuCl(CO)(dppb)(bipy)]PF6 (where, dppb=1,4-bis(diphenylphosphine)butane and bipy=2,2'-bipyridine). The cytotoxic activity of this compound was evaluated against different tumor cell lines (HeLa, human cervical adenocarcinoma; MCF7, human breast adenocarcinoma; MO59J, human glioblastoma; HepG2, hepatocellular carcinoma and B16F10, murine melanoma) and healthy cell line (V79, Chinese hamster lung fibroblasts), by XTT (sodium 2,3'-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-3,4-tetrazolium-bis(4-methoxy-6-nitro)benzene-sulfonic acid hydrate) method. A syngeneic murine melanoma tumor model (B16F10) was used to evaluate its antitumor activity. Additionally, experiments were performed to assess the interactions with ctDNA (calf thymus DNA) and BSA (bovine serum albumin). The results showed that ct-[RuCl(CO)(dppb)(bipy)]PF6 was cytotoxic against all tumor cell lines tested. Furthermore, the compound was more effective against tumor cells compared to the normal cell line, indicating selectivity, especially in B16F10 cells. Significant tumor growth reduction was observed in animals treated with the compound compared to the untreated control. Histopathological analysis of tumor tissue revealed a significant reduction of mitosis in animals treated with the compound compared to the untreated control. In the ctDNA and BSA interaction experiments, the compound in study showed weak interactions with ctDNA and hydrophobic interactions with BSA. The ruthenium compound investigated showed promising results in in vitro and in vivo biological assays. Show less
The new ruthenium(II) complexes with hydrazone ligands, 4-Methyl-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(1)), 4-Methoxy-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(2)), 4-Bro Show more
The new ruthenium(II) complexes with hydrazone ligands, 4-Methyl-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(1)), 4-Methoxy-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(2)), 4-Bromo-benzoic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(3)), were synthesized and characterized by various spectro analytical techniques. The molecular structures of the ligands were confirmed by single crystal X-ray diffraction technique. The DNA binding studies of the ligands and complexes were examined by absorption, fluorescence, viscosity and cyclic voltammetry methods. The results indicated that the ligands and complexes could interact with calf thymus DNA (CT-DNA) through intercalation. The DNA cleavage activity of the complexes was evaluated by gel electrophoresis assay, which revealed that the complexes are good DNA cleaving agents. The binding interaction of the ligands and complexes with bovine serum albumin (BSA) was investigated using fluorescence spectroscopic method. Antioxidant studies showed that the complexes have a strong radical scavenging properties. Further, the cytotoxic effect of the complexes examined on cancerous cell lines showed that the complexes exhibit significant anticancer activity. Show less
The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Show more
The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes. Show less
Ruthenium(II)-arene complexes are promising drug candidates for the therapy of solid tumors. In previous work, seven new compounds of the general formula [Ru(η6-p-cymene)(L1-7)Cl Show more
Ruthenium(II)-arene complexes are promising drug candidates for the therapy of solid tumors. In previous work, seven new compounds of the general formula [Ru(η6-p-cymene)(L1-7)Cl] were synthesized and characterized, of which the complex with L=isoquinoline-3-carboxylic acid (RuT7) was two times as active on HeLa cells compared to normal cell line MRC-5, as indicated by IC50 values determined after 48h of incubation (45.4±3.0 vs. 84.2±5.7μM, respectively). In the present study, cell cycle analysis of HeLa cells treated with RuT7 showed S phase arrest and an increase in sub-G1 population. The apoptotic potential of the title compound was confirmed with the Annexin V-FITC/PI assay together with a morphological evaluation of cells using fluorescent microscopy. Analysis of the intracellular accumulation of ruthenium showed 8.9ng Ru/106 cells after 6h of incubation. To gain further insight in the molecular mechanism of action of RuT7 on HeLa cells, a whole-transcriptome microarray gene expression analysis was performed. Analysis of functional categories and signaling and biochemical pathways associated with the response of HeLa cells to treatment with RuT7 showed that it leads the cells through the intrinsic (mitochondrial) apoptotic pathway, via indirect DNA damage due to the action of reactive oxygen species, and through direct DNA binding of RuT7. Statistical analysis for enrichment of gene sets associated with known drug-induced toxicities identified fewer associated toxicity profiles in RuT7-treated cells compared to cisplatin treatment. Altogether these results provide the basis for further development of RuT7 in animal and pre-clinical studies as a potential drug candidate. Show less
A new pseudo-octahedral π-arene ruthenium(ii) piano-stool compound, containing an O,S-bidentate ligand (compound 1) and showing significant cytotoxic activity in vitro, was synthesized and characteriz Show more
A new pseudo-octahedral π-arene ruthenium(ii) piano-stool compound, containing an O,S-bidentate ligand (compound 1) and showing significant cytotoxic activity in vitro, was synthesized and characterized. In solution stability and interaction with the model protein bovine pancreatic ribonuclease (RNase A) were investigated by using UV-Vis absorption spectroscopy. Its crystal structure and that of the adduct formed upon reaction with RNase A were obtained by X-ray crystallography. The comparison between the structure of purified compound 1 and that of the fragment bound to RNase A reveals an unusual mode of protein binding that includes ligand exchange and alteration of coordination sphere geometry. Show less
The new carbazole N,N' ligand containing [(η(5)-C5Me5)MCl(L)]PF6, (M=Ir (1) and Rh (2)) and [(η(6)-C6H6)RuCl(L)]PF6 (3) (C5Me5=pentamethylcyclopentadienyl, L=9-ethyl-N-(pyridine-2-yl methylene)-9H-car Show more
The new carbazole N,N' ligand containing [(η(5)-C5Me5)MCl(L)]PF6, (M=Ir (1) and Rh (2)) and [(η(6)-C6H6)RuCl(L)]PF6 (3) (C5Me5=pentamethylcyclopentadienyl, L=9-ethyl-N-(pyridine-2-yl methylene)-9H-carbazole-3-amine) complexes has been synthesized and characterized by (1)H NMR, (13)C NMR, 2D NMR, melting point analysis, electronic absorption, infrared spectroscopy, HR-Mass spectroscopy and elemental analyses. The crystal structure of the [(η(5)-C5Me5)RhCl(L)]PF6 has been confirmed by single crystal XRD. The anticancer study of the synthesized complexes 1-3 clearly showed a potent inhibitor of human breast cancer cells (MCF-7) under in vitro conditions. The inhibitory concentrations (IC50) of the complexes 1-3 were determined at low (5, 6 and 8μM) concentration against the MCF-7 human breast cancer cell line. Further cytotoxic, cell cycle and nuclear studies confirmed that the novel half sandwich Ir(III), Rh(III) and Ru(II) complexes could be effective against MCF-7 human breast cancer cell proliferation. Moreover the results indicate that anticancer in vitro activity of complexes 1-3 falls in the order of 1>2>3. A molecular docking study of the complexes 1-3 showed the nature of binding energy, H-bond and hydrophobic interactions with the cyclooxygenase-2 (COX-2) receptor. Show less
Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their devel Show more
Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their development. We have designed a new Ru(II) PDT candidate that efficiently enters cells by incorporation of the lipophilic aromatic pdppz ([2,3-h]dipyrido[3,2-a:2',3'-c]phenazine) ligand and exhibits photoactivity through incorporation of 1,4,5,8-tetraazaphenanthrene ancillary ligands. Its photoreactivity toward biomolecules was studied in vitro, where light activation caused DNA cleavage. Cellular internalization occurred via an energy dependent mechanism. Confocal and transmission electron microscopy revealed that the complex localizes in various organelles, including the mitochondria. The complex is nontoxic in the dark, with cellular clearance within 96 h; however, upon visible light activation it induces caspase-dependent and reactive-oxygen-species-dependent apoptosis, with low micromolar IC50 values. This investigation greatly increases our understanding of such systems in cellulo, aiding development and realization of their application in cancer therapy. Show less
Ruthenium(II)-arene complexes with biotin-containing ligands were prepared so that a novel drug delivery system based on tumor-specific vitamin-receptor mediated endocytosis could be developed. The co Show more
Ruthenium(II)-arene complexes with biotin-containing ligands were prepared so that a novel drug delivery system based on tumor-specific vitamin-receptor mediated endocytosis could be developed. The complexes were characterized by spectroscopic methods and their in vitro anticancer activity in cancer cell lines with various levels of major biotin receptor (COLO205, HCT116 and SW620 cells) was tested in comparison with the ligands. In all cases, coordination of ruthenium resulted in significantly enhanced cytotoxicity. The affinity of Ru(II) -biotin complexes to avidin was investigated and was lower than that of unmodified biotin. Hill coefficients in the range 2.012-2.851 suggest strong positive cooperation between the complexes and avidin. To estimate the likelihood of binding to the biotin receptor/transporter, docking studies with avidin and streptavidin were conducted. These explain, to some extent, the in vitro anticancer activity results and support the conclusion that these novel half-sandwich ruthenium(II)-biotin conjugates may act as biological vectors to cancer cells, although no clear relationship between the cellular Ru content, the cytotoxicity, and the presence of the biotin moiety was observed. Show less
Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a Show more
Aquation has been proposed as crucial chemical action step for ruthenium (Ru) complexes, but its effects on the action mechanisms remain elusive. Herein, we have demonstrated the aquation process of a potent Ru polypyridyl complex (RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , bmbp=2,6-bis(6-methylbenzimidazol-2-yl) pyridine, phen=phenanthroline) with a chloride ligand, and revealed that aquation of RuBmp effectively enhanced its hydrophilicity and cellular uptake, thus significantly increasing its anticancer efficacy. The aquation products (H-RuBmp=[Ru(II) (bmbp)(phen)Cl]ClO4 , [Ru(II) (bmbp)(phen)(H2 O)]ClO4 , bmbp) exhibited a much higher apoptosis-inducing ability than the intact complex, with involvement of caspase activation, mitochondria dysfunction, and interaction with cell membrane death receptors. H-RuBmp demonstrated a higher interaction potency with the cell membrane and induced higher levels of ROS overproduction in cancer cells to regulate the AKT, MAPK, and p53 signaling pathways. Taken together, this study could provide useful information for fine-tuning the rational design of next-generation metal medicines. Show less