The carbonic anhydrase inhibitor acetazolamide (AcmH2) reacted with [(η6-p-cymene)RuCl(μ-Cl)]2 to afford [(η6-p-cymene)RuCl2(κN-AcmH2)], 1A, in near-quantitative yield. In methanol, 1A exists in equil Show more
The carbonic anhydrase inhibitor acetazolamide (AcmH2) reacted with [(η6-p-cymene)RuCl(μ-Cl)]2 to afford [(η6-p-cymene)RuCl2(κN-AcmH2)], 1A, in near-quantitative yield. In methanol, 1A exists in equilibrium with 1B, being probably a coordination isomer, as established by VT 1H-EXSY NMR spectroscopy. DFT calculations pointed to a higher stability of 1A with respect to 1B. [(η6-p-cymene)RuCl(κ2N,N'-AcmH)], 2, was obtained in 86% yield from [(η6-p-cymene)RuCl(μ-Cl)]2 and AcmH2 in the presence of NaOH. The reactions of 2 with AgNO3 (in water), pta/AgNO3 or pta/AgOTf/Et3N (in methanol) afforded the nitrate-coordinated complex [(η6-p-cymene)Ru(κO-NO3)(κ2N,N'-AcmH)], 3, the salt [(η6-p-cymene)Ru(κ2N,N'-AcmH)(κP-pta)]NO3, [4]NO3, and the zwitterion [(η6-p-cymene)Ru(κ2N,N'-Acm)(κP-pta)], 5, respectively, in high yields (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane). The reactions of 5 with Brønsted acids yielded the protonated-pta species [(η6-p-cymene)Ru(κ2N,N'-Acm)(κP-ptaH)]X [6]X (X = NO3, TsO). All compounds were fully characterized by analytical and spectroscopic methods, and the structures of 1A, 2 and 5 were elucidated by X-ray diffraction. The stability of the compounds was investigated in aqueous media and 2 and 5 were evaluated for their cytotoxicity towards human ovarian A2780 and A2780cisR cancer cells and non-tumorigenic HEK-293 cells. Show less
New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η5-MeCp)(PPh3)(4,4'-R-2,2'-bpy)]+ (Ru1, R = H; Ru2, R = CH< Show more
New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η5-MeCp)(PPh3)(4,4'-R-2,2'-bpy)]+ (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P21/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P21/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents. Show less
Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes i Show more
Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD+/NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G0/G1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents. Show less
As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which en Show more
As hypoxia is an important factor to limit chemotherapeutic efficacy in tumors, we herein report three ruthenium(II)-arene complexes containing a hypoxia inducible factor-1α inhibitor (YC-1), which endow the organometallic complexes with potential for hypoxia targeting. In vitro tests showed the resulting complexes had higher anticancer activities in hypoxia than in normoxia against the tested cancer cell lines. Western blot analysis revealed that complexes 1-3 blocked HIF-1α protein accumulation under hypoxic conditions. Moreover, these complexes displayed much less cytotoxicity toward the normal human umbilical vein endothelial cell line (HUVEC), indicating that complexes 1-3 may be selectively cytotoxic for human cancer cell lines. These findings proved that ligation with YC-1 endowed these organometallic ruthenium(II) complexes with potential for hypoxia targeting in addition to enhancing their anticancer activities. Show less
A new family of neutral ruthenium(II) arene complexes of the type [Ru(η6-arene)X(κ2- O, N-L)] (η6-arene = p-cym, bz; X = Cl-, SCN-; HL1 = 2-(2'-h Show more
A new family of neutral ruthenium(II) arene complexes of the type [Ru(η6-arene)X(κ2- O, N-L)] (η6-arene = p-cym, bz; X = Cl-, SCN-; HL1 = 2-(2'-hydroxyphenyl)benzimidazole, HL2 = 2-(2'-hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η6- p-cym)(NCS)(κ2- O, N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ2- O, N-L2)(κ1- S-DMSO)2(μ-SCN)]2 [3c] and [Ru(κ2- O, N-L2)(κ1- S-DMSO)3(SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT). Show less
Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1 Show more
Herein, novel ruthenium(II) complexes containing 1-methylimidazole as a ligand were obtained with the following formulas: [RuCl(1Meim)(dppb)(bpy)]Cl (1), [RuCl(1Meim)(dppb)(4,4'-DMbpy)]Cl (2), [RuCl(1Meim)(dppb)(5,5'-DMbpy)]Cl (3) and [RuCl(1Meim)(dppb)(phen)]Cl (4) where, 1Meim = 1-methylimidazole, dppb = 1,4-Bis(diphenylphosphino)butane, bpy = 2,2'-bipyridine, 4,4'-DMbpy = 4,4'-dimethyl-2,2'-bipyridine, 5,5'-DMbpy = 5,5'-dimethyl-2,2'-bipyridine and phen = 1,10-phenanthroline. Additionally, crystal structures containing the cations of (1) and (3) were obtained when the counter ion was exchanged, leading to the formation of [RuCl(1Meim)(dppb)(bpy)]PF6 (5) and [RuCl(1Meim)(dppb)(5,5'-DMbpy)]PF6 methanol solvate (6) where PF6 = hexafluorophosphate, showing one 1-methylimidazole molecule coordinated through the imidazole nitrogen, as expected. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, 1H, 13C{1H} and 31P{1H} NMR, mass spectrometry and cyclic voltammetry. The interactions of complexes 1-4 with DNA and human serum albumin (HSA) were evaluated, and the cytotoxicity profiles of compounds 1-4 were determined using four different tumor cell lines derived from human cancers (melanoma: HT-144, colon: HCT-8, breast: MDA-MB-231 and lung: A549). A higher cytotoxic activity was observed for compound (3) against non-small cell lung cancer (A549). Complex (3) inhibited the clonogenic capacity and cell cycle progression of A549 cells and induced apoptosis involving mitochondrial pathway activation. Therefore, the data obtained in the present study support further investigations concerning molecular targets of complex (3) in non-small cell lung cancer. Show less
In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino) Show more
In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities. Show less
We report the synthesis, characterization, and antiproliferative activity of organo-osmium(II) and organo-ruthenium(II) half-sandwich complexes [(η6-p-cym)Os(L)Cl]Cl (1 and Show more
We report the synthesis, characterization, and antiproliferative activity of organo-osmium(II) and organo-ruthenium(II) half-sandwich complexes [(η6-p-cym)Os(L)Cl]Cl (1 and 2) and [(η6-p-cym)Ru(L)Cl]Cl (3 and 4), where L = N-(2-hydroxy)-3-methoxybenzylidenethiosemicarbazide (L1) or N-(2,3-dihydroxybenzylidene)-3-phenylthiosemicarbazide (L2), respectively. X-ray crystallography showed that all four complexes possess half-sandwich pseudo-octahedral "three-legged piano-stool" structures, with a neutral N,S-chelating thiosemicarbazone ligand and a terminal chloride occupying three coordination positions. In methanol, E/Z isomerization of the coordinated thiosemicarbazone ligand was observed, while in an aprotic solvent like acetone, partial dissociation of the ligand occurs, reaching complete displacement in a more coordinating solvent like DMSO. In general, the complexes exhibited good activity toward A2780 ovarian, A2780Cis cisplatin-resistant ovarian, A549 lung, HCT116 colon, and PC3 prostate cancer cells. In particular, ruthenium complex 3 does not present cross-resistance with the clinical drug cisplatin in the A2780 human ovarian cancer cell line. The complexes were more active than the free thiosemicarbazone ligands, especially in A549 and HCT116 cells with potency improvements of up to 20-fold between organic ligand L1 and ruthenium complex 1. Show less
Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, an Show more
Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). IrIII complexes showed potent antitumor activity with IC50 values ranged from 3.9 to 11.8 μM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD+ and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G1 or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearson's colocalization coefficient of 0.82 and 0.21 after 12 h, respectively, and followed by an energy-dependent cellular uptake mechanism. Show less
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displayi Show more
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex. Show less
α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic rutheni Show more
α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η6- p-cymene)RuCl{κ2 N-(HCNR)2}]NO3 (R = Cy, [1]NO3; R = 4-C6H10OH, [2]NO3; R = 4-C6H4OH, [3]NO3), were prepared in near-quantitative yields as their nitrate salts. [2]NO3 displays high water solubility. The potential of the α-diimine ligand in [3]NO3 as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η6- p-cymene)RuCl{κ2 N-(HCN(4-C6H4OCO-R))2}]NO3 (R = aspirinate, [5]NO3; valproate, [6]NO3) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO3. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1]+ with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC50 values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO3 and [6]NO3, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO3. Show less
A series of four 2‑amino‑3‑cyano‑4‑(3/4‑pyridyl)‑4H‑benzo[h]chromenes 2a-d and their dichlorido(p‑cymene)ruthenium(II) complexes 3a-d were tested for antiproliferative, vascular-disruptive, anti-angio Show more
A series of four 2‑amino‑3‑cyano‑4‑(3/4‑pyridyl)‑4H‑benzo[h]chromenes 2a-d and their dichlorido(p‑cymene)ruthenium(II) complexes 3a-d were tested for antiproliferative, vascular-disruptive, anti-angiogenic and DNA-binding activity. The coordination of the 4‑pyridyl‑4H‑naphthopyrans 2 to ruthenium led to complexes with pleiotropic effects. Unlike the free ligands 2a-d, their ruthenium complexes 3a-d showed a significant affinity for DNA as demonstrated by electrophoretic mobility shift assays (EMSA) and ethidium bromide assays. Binding of 3a-d to calf thymus DNA proceeded about 10-times faster compared with cisplatin. Treatment of HT-29 colon carcinoma, 518A2 melanoma and MCF-7Topo breast cancer cells with 3a and 3b caused an accumulation of cells in the G2/M phase and an increase of the fraction of mitotic cells in the case of HT-29, due to alterations of the microtubule cytoskeleton as shown by immunofluorescence staining. Complexes 3b-c showed a dual effect on the vascular system. They suppressed angiogenesis in zebrafish embryos and they destroyed the vasculature of the chorioallantoic membrane (CAM) in fertilized chicken eggs. They also inhibited the vasculogenic mimicry, typical of U-87 glioblastoma cells in tube formation assays. Show less
Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-m Show more
Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1 H-pyrazol-5(4 H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance 1H-15N coupling in {1H-15N}-HSQC and {1H-15N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, 1H, and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C═N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin. Show less
Three new iridium (III) complexes [Ir (ppy)2 (ipbc)](PF6) (1), [Ir (bzq)2 (ipbc)](PF6) (2) and [Ir (piq)2 (ipbc)](PF6) (3) were design Show more
Three new iridium (III) complexes [Ir (ppy)2 (ipbc)](PF6) (1), [Ir (bzq)2 (ipbc)](PF6) (2) and [Ir (piq)2 (ipbc)](PF6) (3) were designed and synthesized. All the complexes were tested for anticancer activity using 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The complexes show no cytotoxic activity toward cancer BEL-7402, SGC-7901, Eca-109, A549, HeLa and HepG2 cells. However, upon irradiation with white light, the complexes display high cytotoxicity against BEL-7402 cells with an IC50 value of 5.5 ± 0.8, 7.3 ± 1.3 and 11.5 ± 1.6 μM for 1, 2 and 3, respectively. AO/EB staining and comet assay show that the complexes can induce apoptosis in BEL-7402 cells. The complexes can increase intracellular ROS and Ca2+ levels and cause a decrease in the mitochondrial membrane potential. Autophagic assays exhibit that the complexes can induce autophagy and regulate the expression of Beclin-1 and LC3 proteins. The cell cycle distribution in BEL-7402 cells was carried out by flow cytometry. The expression of Bcl-2 family proteins was studied by western blot. Additionally, the complexes can release cytochrome c and inhibit the polymerization of α-tubulin. Our study reveals that the complexes inhibit the cell growth in BEL-7402 cells through an ROS-mediated mitochondria dysfunction and targeting tubules pathways. These complexes are a promising new entity for the development of multi-target anticancer drugs. Show less
Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(b Show more
Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF6 (1), [Ru(HSpym)(bipy)(dppb)]PF6 (2) and Ru[(SpymMe2)(bipy)(dppb)]PF6 (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120 min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 µM. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC. Show less
Five mononuclear cyclometalated iridium complexes [1](PF6)-[5](PF6) were prepared using imidazole-based ligands of varying alkyl chain length. The complexes were characterised by various analytical te Show more
Five mononuclear cyclometalated iridium complexes [1](PF6)-[5](PF6) were prepared using imidazole-based ligands of varying alkyl chain length. The complexes were characterised by various analytical techniques. The single crystal X-ray structures of [2](PF6), [3](PF6) and [4](PF6) revealed the expected distorted Oh structures around the metal centre; however, the chain length was found to play a crucial role in deciding the overall geometry. Theoretical investigations demonstrated that the HOMOs were mainly contributed by iridium and cyclometalated ligands, whereas the LUMOs were constituted from bpy/phen units. The complexes were found to be luminescent with a moderate emission quantum yield and lifetime in CH3CN. The in vitro growth inhibition assay of the complexes with a shorter alkyl chain ([4]+ and [5]+) displayed higher anticancer activity (IC50 < 0.5 μM) compared to the complexes with a longer alkyl chain ([1]+-[3]+) (IC50 < 30 μM) against human breast cancer (MCF-7) cells. The complexes [4]+ and [5]+ also displayed moderate cancer cell selectivity (∼3 times) over normal breast (MCF-10) cells. The flow cytometry assay and fluorescence microscopy analysis suggested that cellular accumulation was primarily responsible for the variation in anticancer activity. Interestingly, without possessing any anticancer activity or toxicity ((IC50 > 50 μM), the complex [1]+ mainly accumulated near the cell membrane outside the cell and displayed a clear image of the cell membrane. The light microscopy images and western blot analysis reveal that complex [4]+ induced combined apoptosis and paraptosis. Thus, tuning the anticancer activity and cellular imaging property mediated by the alkyl chain would be of great importance and would be useful in anticancer research. Show less
Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model c Show more
Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model compound [Ru(bpy)2(pip)]2+ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline). As shown in the optimized geometry of the complexes, the introduction of styryl group not only extended the conjugated area of the intercalative ligand, but also retained the excellent planarity. These two merits have been proven to be beneficial for their DNA intercalation, thus greatly improved their inhibition activity towards DNA transcription by RNA polymerase and DNA topoisomerase, two enzymes closely related to both DNA and tumor cell growth. The relationships between the substituent group structures and the biological activities have also been investigated from energetic and electronic aspects by quantum chemistry calculations. Results from cell cytotoxicity and apoptosis assay testified that the styryl substituted ruthenium complexes possessed higher antitumor activity than [Ru(bpy)2(pip)]2+, as expected. As quantified in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the tumor cell death is caused mostly through apoptosis for Ru2 and Ru3, while non-apoptotic processes for Ru1, Ru4 and Ru5. In vitro fluorescence evaluation revealed that all complexes located mainly in cytoplasm, but the three complexes with high antiproliferative activity could enter nucleus. All complexes have shown apparent lower cytotoxicity towards normal human colon epithelial cell CCD-841-CON than the examined tumor cell lines. Show less
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, an Show more
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. Show less
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic c Show more
Heterobimetallic compounds are designed to harness chemotherapeutic traits of distinct metal species into a single molecule. The ruthenium-gold (Ru-Au) family of compounds based on Au-N-heterocyclic carbene (NHC) fragments [Cl2(p-cymene)Ru(μ-dppm)Au(NHC)]ClO4 was conceived to combine the known antiproliferative and cytotoxic properties of Au-NHC-based compounds and the antimigratory, antimetastatic, and antiangiogenic characteristic of specific Ru-based compounds. Following recent studies of the anticancer efficacies of these Ru-Au-NHC complexes with promising potential as chemotherapeutics against colorectal, and renal cancers in vitro, we report here on the mechanism of a selected compound, [Cl2(p-cymene)Ru(μ-dppm)Au(IMes)]ClO4 (RANCE-1, 1). The studies were carried out in vitro using a human clear cell renal carcinoma cell line (Caki-1). These studies indicate that bimetallic compound RANCE-1 (1) is significantly more cytotoxic than the Ru (2) or Au (3) monometallic derivatives. RANCE-1 significantly inhibits migration, invasion, and angiogenesis, which are essential for metastasis. RANCE-1 was found to disturb pericellular proteolysis by inhibiting cathepsins, and the metalloproteases MMP and ADAM which play key roles in the etiopathogenesis of cancer. RANCE-1 also inhibits the mitochondrial protein TrxR that is often overexpressed in cancer cells and facilitates apoptosis evasion. We found that while auranofin perturbed migration and invasion to similar degrees as RANCE-1 (1) in Caki-1 renal cancer cells, RANCE-1 (1) inhibited antiangiogenic formation and VEGF expression. We found that auranofin and RANCE-1 (1) have distinct proteolytic profiles. In summary, RANCE-1 constitutes a very promising candidate for further preclinical evaluations in renal cancer. Show less