👤 Anderson R

We report on the synthesis of novel water-soluble [(arene)Ru(II)(Q)Cl] and [(arene)Ru(II)(Q)(X)]BF4 compounds (arene = p-cymene, benzene, hexamethylbenzene; HQ = 1,3-dimethyl-4-R-(C═O)-5-pyrazolone, HQ(Me), R = methyl, HQ(Ph), R = phenyl, HQ(Naph), R = naphthyl; X = H2O, 9-ethylguanine), and their in vitro antitumor activity toward the cell lines MCF7 (HTB-22, human breast adenocarcinoma), HCT116 (CCL-247, human colorectal carcinoma), A2780 (human ovarian carcinoma), A549 (CCL-185, human lung carcinoma), and U87 MG (HTB-1, human glioblastoma). The X-ray crystal structures of two complexes were determined. One of them, {chlorido-(p-cymene)-[(1,3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-ato]ruthenium(II)}, was also studied with density functional theory methods and was selected for docking on a DNA octamer showing intercalation between DNA bases by the naphthyl moiety and for Ru-N7(guanine) bonding. Show less

Novel ruthenium half-sandwich complexes containing (N,O)-bound pyrazolone-based β-ketoamine ligands have been prepared, and the solid-state structures of one ligand and five complexes have been determined by single-crystal X-ray diffraction. Some of the complexes display moderate cytotoxicity toward the human ovarian cancer cell lines A2780 and A2780cisR, the latter line having acquired resistance to cisplatin. Show less

A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed. Show less

A series of ruthenium(II) arene complexes with the 4-(biphenyl-4-carbonyl)-3-methyl-1-phenyl-5-pyrazolonate ligand, and related 1,3,5-triaza-7-phosphaadamantane (PTA) derivatives, has been synthesized. The compounds have been characterized by NMR and IR spectroscopy, ESI mass spectrometry, elemental analysis, and X-ray crystallography. Antiproliferative activity in four human cancer cell lines was determined by MTT assay, yielding dose- and cancer cell line-dependent IC50 values of 9-34 μM for three hexamethylbenzene-ruthenium complexes, whereas the other metal complexes were much less active. Apoptosis was the mechanism involved in the anticancer activity of such compounds. In fact, the hexamethylbenzene-ruthenium complexes activated caspase activity, with consequent DNA fragmentation, accumulation of pro-apoptotic proteins (p27, p53, p89 PARP fragments), and the concomitant down-regulation of antiapoptotic protein Bcl-2. Biosensor-based binding studies indicated that the ancillary ligands were critical in determining the DNA binding affinities, and competition binding experiments further characterized the nature of the interaction. Show less

Over the recent years, several Re(I) organometallic compounds have been shown to be toxic to various cancer cell lines. However, these compounds lacked sufficient selectivity towards cancer tissues to be used as novel chemotherapeutic agents. In this study, we probe the potential of two known N,N-bis(quinolinoyl) Re(I) tricarbonyl complex derivatives, namely Re(I) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-4-butane-1-amine (Re-NH₂) and Re(I) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-5-valeric acid (Re-COOH), as photodynamic therapy (PDT) photosensitizers. Re-NH₂ and Re-COOH proved to be excellent singlet oxygen generators in a lipophilic environment with quantum yields of about 75%. Furthermore, we envisaged to improve the selectivity of Re-COOH via conjugation to two types of peptides, namely a nuclear localization signal (NLS) and a derivative of the neuropeptide bombesin, to form Re-NLS and Re-Bombesin, respectively. Fluorescent microscopy on cervical cancer cells (HeLa) showed that the conjugation of Re-COOH to NLS significantly enhanced the compound's accumulation into the cell nucleus and more specifically into its nucleoli. Importantly, in view of PDT applications, the cytotoxicity of the Re complexes and their bioconjugates increased significantly upon light irradiation. In particular, Re-Bombesin was found to be at least 20-fold more toxic after light irradiation. DNA photo-cleavage studies demonstrated that all compounds damaged DNA via singlet oxygen and, to a minor extent, superoxide production. Show less

A series of half-sandwich Ru(II) arene complexes of the type [Ru(η(6)-arene)(L)Cl](PF6) 1-4, where arene is benzene (1, 2) or p-cymene (3, 4) and L is N-methylhomopiperazine (L1) or 1-(anthracen-10-ylmethyl)-4-methylhomopiperazine (L2), has been isolated and characterized by using spectral methods. The X-ray crystal structures of 2, 3 and 4 reveal that the compounds possess a pseudo-octahedral "piano-stool" structure equipped with the arene ligand as the seat and the bidentate ligand and the chloride ion as the legs of the stool. The DNA binding affinity determined using absorption spectral titrations with CT DNA and competitive DNA binding studies varies as 4 > 2 > 3 > 1, depending upon both the arene and diazacycloalkane ligands. Complexes 2 and 4 with higher DNA binding affinities show strong hypochromism (56%) and a large red-shift (2, 10; 4, 11 nm), which reveals that the anthracenyl moiety of the ligand is stacked into the DNA base pairs and that the arene ligand hydrophobicity also dictates the DNA binding affinity. In contrast, the monocationic complexes 1 and 3 are involved in electrostatic binding in the minor groove of DNA. The enhancement in viscosities of CT DNA upon binding to 2 and 4 are higher than those for 1 and 3 supporting the DNA binding modes of interaction inferred. All the complexes cleave DNA effectively even in the absence of an external agent and the cleavage ability is enhanced in the presence of an activator like H2O2. Tryptophan quenching measurements suggest that the protein binding affinity of the complexes varies as 4 > 2 > 3 > 1, which is the same as that for DNA binding and that the fluorescence quenching of BSA occurs through a static mechanism. The positive ΔH(0) and ΔS(0) values for BSA binding of complexes indicate that the interaction between the complexes and BSA is mainly hydrophobic in nature and the energy transfer efficiency has been analysed according to the Förster non-radiative energy transfer theory. The variation in the ability of complexes to cleave BSA in the presence of H2O2, namely, 4 > 2 > 3 > 1, as revealed from SDS-PAGE is consistent with their strong hydrophobic interaction with the protein. The IC50 values of 1-4 (IC50: 1, 28.1; 2, 23.1; 3, 26.2; 4, 16.8 μM at 24 h; IC50: 1, 19.0; 2, 15.9; 3, 18.1; 4, 9.7 μM at 48 h) obtained for MCF 7 breast cancer cells indicate that they have the potency to kill cancer cells in a time dependent manner, which is similar to cisplatin. The anticancer activity of complexes has been studied by employing various biochemical methods involving different staining agents, AO/EB and Hoechst 33258, which reveal that complexes 1-4 establish a specific mode of cell death in MCF 7 breast cancer cells. The comet assay has been employed to determine the extent of DNA fragmentation in cancer cells. Show less

An efficient drug delivery strategy is presented for novel anticancer amphiphilic ruthenium anionic complexes, based on the formation of stable nanoparticles with the cationic lipid 1,2-dioleyl-3-trimethylammoniumpropane chloride (DOTAP). This strategy is aimed at ensuring high ruthenium content within the formulation, long half-life in physiological media, and enhanced cell uptake. An in-depth microstructural characterization of the aggregates obtained mixing the ruthenium complex and the phospholipid carrier at 50/50 molar ratio is realized by combining a variety of techniques, including dynamic light scattering (DLS), small angle neutron scattering (SANS), neutron reflectivity (NR), electron paramagnetic resonance (EPR), and zeta potential measurements. The in vitro bioactivity profile of the Ru-loaded nanoparticles is investigated on human and non-human cancer cell lines, showing IC(50) values in the low μM range against MCF-7 and WiDr cells, that is, proving to be 10-20-fold more active than AziRu, a previously synthesized NAMI-A analog, used for control. Fluorescence microscopy studies demonstrate that the amphiphilic Ru-complex/DOTAP formulations, added with rhodamine-B, are efficiently and rapidly incorporated in human MCF-7 breast adenocarcinoma cells. The intracellular fate of the amphiphilic Ru-complexes was investigated in the same in vitro model by means of an ad hoc designed fluorescently tagged analog, which exhibited a marked tendency to accumulate within or in proximity of the nuclei. Show less

The synthesis and characterization of cationic ruthenium(II) complexes of the type [Ru(η(6)-p-cym)Cl{Ph(2)P(CH(2))(n)S(O)(x)Ph-κP,κS}][PF(6)] (n = 1-3; x = 0, 1; p-cym = p-cymene) are presented. Furthermore, their high biological potential even against cisplatin-resistant tumor cell lines and their structure-activity relationships are discussed. Show less

A series of hexa-coordinated ruthenium(II) complexes of the type [Ru(CO)(B)L(n)] (n = 1-4; B = PPh3, AsPh3 or Py) have been synthesized by reacting dibasic quadridentate Schiff base ligands H2L(n) (n = 1-4) with starting complexes [RuHCl(CO)(EPh3)2(B)] (E = P or As; B = PPh3, AsPh3 or Py). The synthesized complexes were characterized using elemental and various spectral studies including UV-Vis, FT-IR, NMR ((1)H, (13)C and (31)P) and mass spectroscopy. An octahedral geometry was tentatively proposed for all the complexes based on the spectral data obtained. The experiments on antioxidant activity showed that the ruthenium(II) S-methylisothiosemicarbazone Schiff base complexes exhibited good scavenging activity against various free radicals (DPPH, OH and NO). The in vitro cytotoxicity of these complexes has been evaluated by MTT assay. The results demonstrate that the complexes have good anticancer activities against selected cancer cell line, human breast cancer cell line (MCF-7) and human skin carcinoma cell line (A431). The DNA cleavage studies showed that the complexes have better cleavage of pBR 322 DNA. Show less

Two ruthenium(II) polypyridyl complexes, [Ru(bpy)(2)(ptpn)](2+) (1) (bpy = 2,2'-bipyridine, ptpn = 3-(1,10-phenanthroline-2-yl)-as-triazino[5,6-f]1,10-phenanthroline) and [Ru(phen)(2)(ptpn)](2+) (2) (phen = 1,10-phenanthroline), were synthesized and characterized. Crystal structure analysis shows that complex 1 has a large planar aromatic area and possesses the potential to fit the geometric structure of G-quadruplex. The interaction of the G-quadruplex DNA with Ru(ii) complexes was explored by means of circular dichroism (CD), fluorescence resonance energy transfer (FRET) melting assay, competitive FRET assay and polymerase chain reaction (PCR) stop assay. The results indicated that complexes 1 and 2 both have the ability to promote the formation and stabilization of the human telomeric d[(TTAGGG)(n)] (HTG22) quadruplex and exhibit high G-quadruplex DNA selectivity over duplex DNA. The telomere repeat amplification protocol (TRAP) assay and long-term proliferation experiments further demonstrate that the Ru(II) complexes are potent telomerase inhibitors and HeLa cell proliferation inhibitors. Show less

The cellular behavior and toxicity effect of organometallic complexes depend largely on their peripheral ligands. In this study, we have synthesized a series of novel luminescent cationic iridium(III) complexes by tuning the ancillary N(∧)N ligand based on a structure [Ir(ppy)2(N(∧)N)](+) (ppy = 1-phenyl-pyridine; N(∧)N = 2,2'-bipyridine (bpy, 1) or phenanthroline (phen, 2) or 4,7-diphenyl-1,10- phenanthroline (DIP, 3)). As the size of coordinated N(∧)N ligand increases, absorbance/emission efficiency, quantum yields, lipophilicity, and cell uptake rates of the complexes also increase, in a general order: 3 > 2 > 1. All three complexes display anticancer activity, with 3 exhibiting the highest cellular uptake efficiency and the greatest cytotoxic activities in several cancer cell lines with IC50s lower than that of cisplatin. Because of its strong hydrophobic nature, the death inducer 3 was found to accumulate favorably to endoplasmic reticulum (ER) and to cause ER stress in cells. The fast cytosolic release of calcium from stressed ER disturbed the morphology and function of mitochondria, initiating an intrinsic apoptotic pathway. Understanding of the cell death mechanism would help further structure-activity optimization on these novel Ir(III) complexes as emerging cancer therapeutics. Show less

The in vitro antiproliferative activity of the title compound on five tumor cell lines shows preference for the colon-rectal tumor HCT116, IC(50) = 13.98 μM, followed by breast MCF7 (19.58 μM) and ovarian A2780 (23.38 μM) cell lines; human glioblastoma U-87 and lung carcinoma A549 are less sensitive. A commercial curcumin reagent, also containing demethoxy and bis-demethoxy curcumin, was used to synthesize the title compound, and so (p-cymene)Ru(demethoxy-curcuminato)chloro was also isolated and chemically characterized. The crystal structure of the title compound shows (1) the chlorine atom linking two neighboring complexes through H-bonds with two O(hydroxyl), forming an infinite two-step network; (2) significant twist in the curcuminato, 20° between the planes of the two phenyl rings. This was also seen in the docking of the Ru-complex onto a rich guanine B-DNA decamer, where a Ru-N7(guanine) interaction is detected. This Ru-N7(guanine) interaction is also seen with ESI-MS on a Ru-complex-guanosine derivative. Show less

Reactions of ω-diphenylphosphino-functionalized alkyl phenyl sulfides Ph(2)P(CH(2))(n)SPh (n=1, L1; 2, L2; 3, L3), sulfoxides Ph(2)P(CH(2))(n)S(O)Ph (n=1, L4; 2, L5; 3, L6) and sulfones Ph(2)P(CH(2))(n)S(O)(2)Ph (n=1, L7; 2, L8; 3, L9) with the dinuclear chlorido bridged ruthenium(II) complex [{Ru(η(6)-p-cymene)Cl(2)}(2)] afforded mononuclear ruthenium(II) complexes of the type [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(n)S(O)(x)Ph-κP}] (n/x=1/0, 1; 2/0, 2; 3/0, 3; 1/1, 4; 2/1, 5; 3/1, 6; 1/2, 7; 2/2, 8; 3/2, 9) having the P(∩)S(O)(x) ligands κP coordinated. The complexes were characterized by (1)H, (13)C and (31)P NMR spectroscopy. The crystal structures of complexes 2, 7·CH(2)Cl(2) and 8 were determined by X-ray diffraction analysis. All complexes have been screened for cytostatic activity against cell lines 518A2, 8505C, A253, MCF-7, and SW480. In vitro biological experiments demonstrate that these compounds are active toward the used cell lines. The ruthenium(II) complex [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(2)SPh-κP}] (2) is the most active compound in the human cancer cell line MCF-7 with the IC(50) value 1.4 μM lower than cisplatin (2.0 μM). Show less

Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported. Show less

Aminophosphines 2-(diphenylphosphino)-1-methylimidazole (dpim) and diphenyl-2-pyridylphosphine (PPh(2)py) have been used to prepare two series of Ru(II) arene complexes of formulae [(η(6)-p-cymene)Ru(κ(2)-O,O'-X)(κ(1)-P-dpim)]Y (series a: 1a·Y-3a·Y) and [(η(6)-p-cymene)Ru(κ(2)-O,O'-X)(κ(1)-P-PPh(2)py)]Y (series b: 1b·Y-3b·Y) (where X=acac, acetylacetonate; bzac, benzoyl acetonate; dbzm, dibenzoyl methanoate; Y=BF(4), BPh(4)). The structures of 1a·BF(4), 1a·BPh(4), 3a·BF(4), 1b·BPh(4) and 3b·BPh(4) were determined by X-ray diffraction. The tetrafluoroborate derivatives are more soluble in organic solvents than their tetraphenylborate counterparts. Five BF(4)(-) derivatives (all except the unstable 1b·BF(4)) were selected to evaluate the cytotoxic behavior in vitro against the human cancer cell lines MCF-7 (breast cancer) and CAPAN-1 (pancreatic cancer). 2b·BF(4) and 3b·BF(4) exhibited IC(50) values similar to those of cisplatin. Electrophoresis and AFM studies showed good correspondence between the biological activity levels of 2b·BF(4) and 3b·BF(4) and their ability to modify the DNA structure. Hydrolytic studies indicate that aquation could be involved in the activation mechanism of these complexes and confirm that the hydrolysis rate of 3b·BF(4) is higher than that of 3a·BF(4). Thus, the cytotoxic activity trends are explained in terms of the higher reactivity of derivatives from series b, which in turn is rationalized as being the result of the electronic features of dpim and PPh(2)py established by cyclic voltammetry measurements. Show less

Neutral half-sandwich organometallic ruthenium(II) complexes of the type [(η(6)-cymene)RuCl(2)(L)] (H1-H10), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single-crystal X-ray diffraction confirming a piano-stool geometry with η(6) coordination of the arene ligand. Hydrogen bonding between the N-H group of the heterocycle and a chlorine atom attached to Ru stabilizes the metal-ligand interaction. Complexes coordinated to a mercaptobenzothiazole framework (H1) or mercaptobenzoxazole (H6) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1-phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non-intercalative fashion and cause unwinding of plasmid DNA in a cell-free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIα activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen-bond donor on the heterocycle reduces the cytotoxicity. Show less

Half-sandwich organorhodium(III) complexes and their trichloridorhodium(III) counterparts are potent anticancer agents that enhance the formation of reactive oxygen species and invoke a strong induction of apoptosis in leukemia cells. The antiproliferative activity towards human MCF-7 and HT-29 adenocarcinoma cells of novel nonintercalating complexes containing the 5-substituted phenanthroline ligands 5,6-dimethylphenanthroline, 5-chlorophenanthroline, and 5-nitrophenanthroline (phen*) increases dramatically in the order [(η(5)-C(5)Me(5))IrCl(phen*)](CF(3)SO(3)) < [(η(5)-C(5)Me(5))RhCl(phen*)](CF(3)SO(3)) < mer-[RhCl(3)(DMSO)(phen*)] (DMSO is dimethyl sulfoxide). Improved activity was also achieved by attaching a cell-penetrating peptide to the dipyrido[3,2-a:2',3'-c]phenazine (dppz) ligand of an organorhodium(III) complex. Whereas 5-substitution led to significant improvements in the activity of the organoiridium(III) and trichloridorhodium(III) compounds in comparison with the parent phenanthroline complex, the IC(50) values of their organorhodium(III) counterparts remained effectively invariable. The high activities of the trichloridorhodium(III) complexes (IC(50) = 0.06-0.13 μM) were accompanied by pronounced selectivity towards human cancer cells in comparison with immortalized HEK-293 cells. In contrast, [(η(5)-C(5)Me(5))RhCl(5,6-Me(2)phen)](CF(3)SO(3)) (phen is phenanthroline) was markedly more active towards BJAB lymphoma cells than ex vivo healthy leukocytes and caused an immediate decrease in cellular adhesion possibly associated with interactions with membrane proteins. Its dppz analogue invoked an initial increase in glycolysis to compensate for reduced respiration before inducing a delayed onset of cell death. Strong antimitochondrial activity with respiration impairment and release of cytochrome c was established for both complexes. Show less

The 1.7 Å X-ray crystal structure of the B-DNA dodecamer, [d(CGCGAATTCGCG)]₂ (DDD)-bound non-covalently to a platinum(II) complex, [{Pt(NH₃)₃}₂-µ-{trans-Pt(NH₃)₂(NH₂(CH₂)₆NH₂)₂}](NO₃)₆ (1, TriplatinNC-A,) shows the trinuclear cation extended along the phosphate backbone and bridging the minor groove. The square planar tetra-am(m)ine Pt(II) units form bidentate N-O-N complexes with OP atoms, in a Phosphate Clamp motif. The geometry is conserved and the interaction prefers O2P over O1P atoms (frequency of interaction is O2P > O1P, base and sugar oxygens > N). The binding mode is very similar to that reported for the DDD and [{trans-Pt(NH₃)₂(NH₂(CH₂)₆(NH₃(+))}₂-µ-{trans-Pt(NH₃)₂(NH₂(CH₂)₆NH₂)₂}](NO₃)₈ (3, TriplatinNC), which exhibits in vivo anti-tumour activity. In the present case, only three sets of Phosphate Clamps were found because one of the three Pt(II) coordination spheres was not clearly observed and was characterized as a bare Pt²(+) ion. Based on the electron density, the relative occupancy of DDD and the sum of three Pt(II) atoms in the DDD-1 complex was 1:1.69, whereas the ratio for DDD-2 was 1:2.85, almost the mixing ratio in the crystallization drop. The high repetition and geometric regularity of the motif suggests that it can be developed as a modular nucleic acid binding device with general utility. Show less

In our previous study, ruthenium(II)-p-cymene complexes of general formula [(η(6)-p-cymene)Ru(L)Cl2], L: 3-acetylpyridine (1), 2-amino-5-chloropyridine (2); and [(η(6)-p-cymene)Ru(HL)Cl], HL: 2,3-pyridinedicarboxylic acid (3), 2,4-pyridinedicarboxylic acid (4), revealed low antiproliferative activity, except complex [(η(6)-p-cymene)RuCl(picolinic acid)]·H(2)O (5) which exhibited IC(50) around 80 μM. In this study we further investigated in vitro potential of antimetastatic action of ruthenium complexes on HeLa and two endothelial cell lines. Comparison of structure and activity of five complexes indicated heterogenic mode of activity, with regard to the potential of antimetastatic and antiproliferative effect. Replacement of substituted pyridine ligand with picolinic acid (complex 5) around Ru(II) center contributed to complex cytotoxicity and ruthenium DNA binding affinity. Analysis of ruthenium(II) accumulation in DNA and protein fractions of HeLa cells, using ICP-OES revealed significantly higher content of complex 5 in DNA fraction in comparison to the other tested compounds. It also altered cell cycle progression, affected expression of DNA repair enzymes ERCC1 and MSH2, and showed enhanced activity in combination with 3-aminobenzamide. Regardless of their effect on cell growth, Ru(II) complexes exerted antimetastatic effect on several tumor cell lines in vitro, achieved mostly by the effect on cell adhesion, migration and angiogenesis, while picolinate ruthenium(II)-arene additionally exerted inhibitory effect on extracellular matrix degradation. Show less

A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl(4)(DMSO)(n-Cl-LH)]⋅xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)]·xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)]·xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH-LH)]·xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl(4)(DMSO)(3-Br-LH)]⋅(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100μM in contrast to the moderate results regarding the antiradical activity with IC(50)≈10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ. Show less

The antiproliferative properties and biological impact of octahedral iridium(III) complexes of the type fac-[IrCl3 (DMSO)(pp)] containing pp=phenanthroline (1) and its 4- and 5-methyl (2, 3) and 4,7- and 5,6-dimethyl derivatives (4, 5) were investigated for both adherent and non-adherent cells. A series of similar rhodium(III) complexes were studied for comparison purposes. The antiproliferative activity toward MCF-7 cancer cells increases eightfold from IC50=4.6 for 1 to IC50=0.60 μM for 5, and an even more pronounced 18-fold improvement was established for the analogous rhodium complexes 6 and 8, the respective IC50 values for which are 1.1 and 0.06 μM. Annexin V/propidium iodide assays demonstrated that the 5,6-dimethylphenanthroline complexes 5 and 8 both cause significant inhibition of Jurkat leukemia cell proliferation and invoke extensive apoptosis but negligible necrosis. The percentages of Jurkat cells exhibiting high levels of reactive oxygen species correlate with the percentages of cells undergoing apoptosis. The antiproliferative activity of 5 and 8 is strongly selective toward MCF-7 and HT-29 cancer cells over normal HFF-1 and immortalized HEK-293 cells. Complex 5 also exhibits high selectivity toward BJAB lymphoma cells relative to healthy leukocytes. Both 5 and 8 invoke permanent decreases in the adhesion and respiration of MCF-7 cells. Show less

The cytostatic properties of novel rhodium(III) thiacrown ether complexes [RhCl(LL)([9]aneS(3))](n+) with either aromatic κ(2)N ligands (n = 2) or anionic chelate ligands (n = 1) have been investigated for the human cancer cell lines HT-29 and MCF-7 and for immortalized HEK-293 cells. Taken together with literature IC(50) values for analogous complexes with polypyridyl ligands or 1,4-dithiane, the in vitro assays indicate that dicationic complexes with soft κ(2)N (imino) or κ(2)S (thiaether) ligands exhibit significantly higher antiproliferative effects than those with hard κ(2)N (amino) ligands. Dicationic complexes are more active than monocationic complexes with similar ligands. Pronounced apoptosis-inducing properties towards Jurkat cells were established for complexes with LL = bpm, dpq, and 1,4-dithiane. The order of activity (bpm > 1,4-dithiane > dpq > bpy) contrasts to that observed for adhesive cancer cells (bpm > bpy, 1,4-dithiane > dpq). Necrosis is insignificant in all cases. The percentage of Jurkat cells exhibiting apoptosis after 24 or 48 h incubation periods is directly correlated to the percentage of cells exhibiting high levels of reactive oxygen species. As established by online monitoring with a sensor chip system, treatment of MCF-7 cells with the bpm and 1,4-dithiane complexes leads to a significant and permanent concentration-dependent decrease in oxygen consumption and cellular adhesion. Show less

We have previously showed that platinum drugs up-regulate SSAT and SMO and down-regulate ODC and SAMDC in the polyamine pathway. Several studies including our own established that platinum drugs combined with polyamine analog DENSPM produces synergistic increase in SSAT activity with polyamine depletion. Since polyamine pathway is an important therapeutic target, we investigated whether agents containing both platinum and polyamines have similar effects on the polyamine pathway. Two complexes i) Pt-spermine with two cisplatin molecules linked to a spermine in the center and ii) Pd-spermine with similar structure i, but Pd (II) substituted for Pt (II) were analyzed with respect to their effect on the expression of genes in polyamine pathway, SSAT and SMO protein expression, SSAT activity and polyamine pools. Pt-, Pd-spermine complexes induced significant down-regulation of SMO, arginase 2 and NRF-2, with no change in SSAT, while cisplatin as a single agent or in combination with DENSPM induced significant up-regulation of SSAT and SMO. The SSAT activity was not induced by either Pt- or Pd-spermine in A2780 cells; SMO protein levels were significantly elevated compared to the no-drug control and to a similar extent as cisplatin/DENSPM. The Pd-spm treatment induced a fall in putrescine levels to 33%, spermidine to 62% and spermine to 72% while Pt-spm did not induce such a decline. Comparative cytotoxicity studies in A2780 cells indicated the potency to be cisplatin> Pd-Spm>Pt-Spm. Although both complexes exhibit a lower potency, the degree of resistance itself is much lower for Pt-spermine and Pd-spermine in that order (2.5 and 7.5, respectively) compared to cisplatin ( approximately 12) as tested in cisplatin resistant A2780/CP cells. These studies suggest that Pd (II)-polyamine complexes may constitute a promising group of inorganic compounds for further studies in the development of novel chemotherapy/adjuvant chemotherapy strategies. Show less

The synthesis and full characterization of new half-sandwich ruthenium(II) complexes containing κ(3)(N,N,N)-hydridotris(pyrazolyl)borate (κ(3)(N,N,N)-Tp) and the water-soluble phosphanes 1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]decane (PTA) and 1-methyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1(3,7)]decane (1-CH(3)-PTA) has been explored. Single crystal X-ray diffraction analysis for complex [RuCl{κ(3)(N,N,N)-Tp}(PMe(2)Ph)(1-CH(3)-PTA)][CF(3)SO(3)]·2NCMe is also reported. DNA binding properties of the ruthenium complexes have been evaluated by mobility shift assay and MALDI-TOF mass spectrometry. The in vitro antitumor activity of these compounds was assessed by examining their ability to inhibit cell proliferation in a number of human cancer cell lines (NCI-H460, SF-268, MCF-7) and non-tumor human umbilical vein endothelial cells (HUVEC). Some of these new compounds show promising cytotoxic activity with IC(50) values in the low micromolar range, and display differential effects on cancer and normal cell growth. Show less

Half-sandwich rhodium(III) polypyridyl (pp) complexes with the metal atom capped by the facial crown thiaether 1,4,7-trithiacyclononane [9]aneS(3) represent a promising class of apoptosis-inducing potent cytostatic agents. The necrotic damage caused by the complexes is negligible. In vitro cytotoxicity assays with the human cancer cell lines MCF-7 and HT-29 and immortalized HEK-293 cells indicate that the dicationic kappa(2)N(imino) complexes [([9]aneS(3))RhCl(pp)](2+) are much more active than monocationic complexes [([9]aneS(3))RhCl(2)(L)](+) (L=imidazole, CH(3)CN). Whereas the kappa(2)N(amino) complex [([9]aneS(3))RhCl(piperazine)](2+) is inactive, replacing piperazine with the structurally analogous kappa(2)S (thiaether) ligand 1,4-dithiane restores cytotoxicity as evidenced by IC(50) values in the range 8.1-11.6 microM. Spectroscopic (CD, UV/Vis, NOESY) and viscosity measurements indicate that the active dppz complex 8 (IC(50) values: 4.7-8.9 microM) exhibits strong intercalative binding towards DNA whereas the even more potent bipyrimidine complex 9 (IC(50) values: 0.6-1.9 microM) causes no alteration of the duplex B conformation. Weaker intercalative binding is observed for the dpq complex 7. A comparative annexin V-propidium iodide binding assay with lymphoma (BJAB) cells and healthy leukocytes demonstrates that the cytotoxic activity of complex 8 and particularly complex 9 is highly selective towards the malignant cells. Show less

Neutral and cationic organometallic ruthenium(II) piano stool complexes of the type [(eta(6)-cymene)RuCl(X)(Y)] (complexes R1-R8) has been synthesized and characterized. In cationic complexes, X, Y is either a eta(2) phosphorus ligand such as 1,1-bis(diphenylphosphino)methane (DPPM) and 1,2-bis(diphenylphosphino)ethane (DPPE) or partially oxidized ligands such as 1,2-bis(diphenylphosphino)methane monooxide (DPPMO) and 1,2-bis(diphenylphosphino)ethane monooxide (DPPEO) which are strong hydrogen bond acceptors. In neutral complexes, X is chloride and Y is a monodentate phosphorous donor. Complexes with DPPM and DPPMO ligands ([(eta(6)-cymene)Ru(eta(2)-DPPM)Cl]PF(6) (R2), [(eta(6)-cymene)Ru(eta(2)-DPPMO)Cl]PF(6) (R3), [(eta(6)-cymene)Ru(eta(1)-DPPM)Cl(2)] (R5) and [(eta(6)-cymene)Ru(eta(1)-DPPMO)Cl(2)] (R6) show good cytotoxicity. Growth inhibition study of several human cancer cell lines by these complexes has been carried out. Mechanistic studies for R5 and R6 show that inhibition of cancer cell growth involves both cell cycle arrest and apoptosis induction. Using an apoptosis PCR array, we identified the sets of anti-apoptotic genes that were down regulated and pro-apoptotic genes that were up regulated. These complexes were also found to be potent metastasis inhibitors as they prevented cell invasion through matrigel. The complexes were shown to bind DNA in a non intercalative fashion and cause unwinding of plasmid DNA in cell-free medium by competitive ethidium bromide binding, viscosity measurements, thermal denaturation and gel mobility shift assays. Show less

The organoruthenium complex [(eta(6)-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(eta(6)-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(eta(6)-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC(50) 24 microM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269-18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5'-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution. Show less

Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC(50) values of 1 and 2 toward HT-29 cells increase from 0.19 and 0.069 microM on immediate use in the dark to 0.66 and 0.312 microM, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer-[IrX(3)(DMSO)(phen)] (X=Cl 7, Br 8) are significantly less cytotoxic than their facial Ir(III) polypyridyl counterparts: IC(50)=20.3 microM for 7 and 4.6 microM for fac-[IrCl(3)(DMSO)(phen)] 5 toward MCF-7 cells. The IC(50) values for the complexes fac-[IrX(3)(L)(pp)] 9-13 decrease in the orders: a) Cl>Br for X and b) H(2)O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM-6) and lymphoma (BJAB) cells after incubation with 2, 3, and 11 (X=Br, L=H(2)O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible. Show less

The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS(3))](2+) [(pp)=2,2'-bipyridine (bpy), 2,2'-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), dipyrido[2,3-a:2',3'-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl(3).3H(2)O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2 [IC(50) values: 12.8 (+/-0.2) and 4.4 (+/-0.1)microM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC(50) values: 36.3 (+/-6.0) and 72.2 (+/-8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC(50) values of 72.2 (+/-8.0), 20.9 (+/-2.8) and 7.4 (+/-2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC(50) values: 1.7 (+/-0.5) and 1.9 (+/-0.1)microM] and tap (5) [IC(50) values: 11.5 (+/-0.6) and 7.6 (+/-4.8)microM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved. Show less