👤 Barzowska A

A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate. 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

Ru(II)(arene) anticancer compounds with maleimide functionality were prepared to allow selective interaction with thiol-containing biomolecules and thereby enforcing the selective delivery of the compounds to the tumour. Show less

The cytostatic properties and cellular effects of novel diene-ruthenium(II) complexes of the types OC-6-13-[RuCl(2)(pp)(cod)] 1-5 (pp=2,2'-bipyridyl (bpy), phen=1,10-phenanthroline (phen), 5,6-dimethylphenanthroline (5,6-Me2phen), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), ethylenediamine (en)) and OC-6-24-[RuCl{(Me(2)N)(2)CS}(pp)(cod)](CF(3)SO(3)) 6-8 (pp=phen, 5,6-Me(2)phen, dpq) have been studied for the human cancer cell lines MCF-7 and HT-29 and for Jurkat leukemia cells. CD spectra indicate that 7 causes a massive distortion of the CT DNA B double helix toward the A form. Whereas the neutral complexes 1, 2 and 5 exhibit only modest antiproliferative activity toward MCF-7 and HT-29 cells, the monocationic complexes are significantly more active, in particular the DNA-distorting complex 7 with its IC(50) values of 0.73 and 0.42 μM, respectively. As established by online monitoring with a cell-based sensor chip, this potent 5,6-Me(2)phen complex invokes dose-dependent decreases in MCF-7 cellular respiration and extracellular acidification rates and causes a time-delayed decrease in the impedance of the cell layers, that can be ascribed to cell death. Treatment of Jurkat cells with 7 leads to high concentrations of reactive oxygen species and the induction of apoptosis. The pronounced dose-dependent inhibition of oxygen consumption by isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in the programmed cell death process. Show less

Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (1c-5c) of the general formula [RuCl(η(6)-arene)(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η(6)-benzylamide and L is a Cdk inhibitor [3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) and indolo[3,2-d]benzazepines (L4 and L5)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2-3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of 1c and 2c(-HCl) afforded residues, which after recrystallization from EtOH and EtOH/H(2)O, respectively, were shown by X-ray diffraction to be cis,cis-[Ru(II)Cl(2)(DMSO)(2)(L1)]·H(2)O and mer-[Ru(II)Cl(DMSO)(3)(L2-H)]·H(2)O. Compound 5c, with a coordinated amidine unit, undergoes E/Z isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes 1c-5c are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, 1c-5c were conjugated to recombinant human serum albumin, potentially exploiting the so-called "enhanced permeability and retention" effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases. Show less

Six organometallic complexes of the general formula [M(II)Cl(η(6)-p-cymene)(L)]Cl, where M = Ru (11a, 12a, 13a) or Os (11b, 12b, 13b) and L = 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV-vis spectroscopy, ESI mass spectrometry, and X-ray crystallography (11b and 12b). The multistep synthesis of 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (3) via 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2); the synthesis of 1-methoxymethyl-2,3-diaminobenzene (5) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acids (1, 3) through the use of an inexpensive coupling reagent, N,N'-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted L3 by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b-L3 and 4b'-L3 in a metal-free state are described. Structure-activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported. Show less

The synthesis and characterization of a number of organometallic ruthenium(II) complexes containing a series of bidentate thiosemicarbazone ligands derived from piperonal is reported. The structure of compounds have been confirmed by spectroscopic analysis (IR and NMR) as well as X-ray crystallographic analysis of [(η⁶-p-cymene)Ru(pPhTSC)Cl]Cl (4) (pPhTSC is piperonal-N(4)-phenylthiosemicarbazone). The interaction of the complexes ([(η⁶-p-cymene)Ru(pEtTSC)Cl]Cl) (3) (pEtTSC is piperonal-N(4)-ethylthiosemicarbazone) and 4 with calf thymus DNA, human serum albumin (HSA) and pBR322 plasmid DNA were studied by spectroscopic, gel electrophoresis and hydrodynamic methods. The apparent binding constant for the interaction with DNA was determined to be 3.97×10³ M⁻¹ and 4.07×10³ M⁻¹ at 293 K for 3 and 4 respectively. The complexes bind strongly to HSA with binding constants of 2.94×10⁴ M⁻¹ and 12.2×10⁴ M⁻¹ at 296 K for 3 and 4 respectively. The in vitro anticancer activity of 3 and 4 has been evaluated against two human colon cancer cell line (HCT-116 and Caco-2) with IC50 values in the range of 26–150 μM. Both 3 and 4 show good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 μM. The proficiency of 3 and 4 to act as antibacterial agents was also evaluated against six pathogenic bacterial strains with the best activity seen against Gram-positive strains. Show less

We have used a novel microwave-assisted method developed in our laboratories to synthesize a series of ruthenium-thiosemicarbazone complexes. The new thiosemicarbazone ligands are derived from benzo[d][1,3]dioxole-5-carbaldehyde (piperonal) and the complexes are formulated as [(diimine)(2)Ru(TSC)](PF(6))(2) (where the TSC is the bidentate thiosemicarbazone ligand). The diimine in the complexes is either 2,2'-bipyridine or 1,10-phenanthroline. The complexes have been characterized by spectroscopic means (NMR, IR and UV-Vis) as well as by elemental analysis. We have studied the biophysical characteristics of the complexes by investigating their anti-oxidant ability as well as their ability to disrupt the function of the human topoisomerase II enzyme. The complexes are moderately strong binders of DNA with binding constants of 10(4) M(-1). They are also strong binders of human serum albumin having binding constants on the order of 10(4) M(-1). The complexes show good in vitro anticancer activity against human colon cancer cells, Caco-2 and HCT-116 and indeed show some cytotoxic selectivity for cancer cells. The IC(50) values range from 7 - 159 μM (after 72 h drug incubation). They also have antibacterial activity against Gram-positive strains of pathogenic bacteria with IC(50) values as low as 10 μM; little activity was seen against Gram-negative strains. It has been established that all the compounds are catalytic inhibitors of human topoisomerase II. Show less

Herein we describe the synthesis, characterization, and anticancer activity of novel p-cymeneruthenium(II) complexes containing methyl, ethyl, n-propyl, and n-butyl esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, (1)H, and (13)C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL-60, K562, and REH cells (IC(50): 1.0-20.2 μM), with the n-butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n-butyl ester complex is more effective against leukemic patients' blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of Ru(II)-based compounds. Show less

The new monofunctional Ru(II)-arene complex [(η⁶-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.2008, 51, 5310). The present study is focused on the cellular pharmacology of 1 to elucidate more deeply the mechanisms underlying its antitumor effects. We have identified several cellular mechanisms induced by 1 in human ovarian carcinoma cells, including inhibition of DNA synthesis, overexpression and activation of p53, expression of proapoptotic proteins p21(WAF1) and Bax, G₀/G₁ arrest, and nuclear fragmentation as a result of apoptotic, and, to a much lower extent, also necrotic processes. Thus, 1 inhibits growth of the cancer cells through induction of apoptotic cell death and G₀/G₁ cell cycle arrest. Further investigations have shown that 1 induces apoptosis by regulating the expression of Bcl-2 family proteins. There were significant differences in cellular responses to the treatment with 1 and with conventional cisplatin, particularly in the kinetics and the extent of these responses. In addition, the distinct p53 activation profile of 1 compared with cisplatin provides an explanation for the activity of this ruthenium drug against cisplatin-resistant cells. Hence complex 1 may provide an alternative therapy in patients with acquired cisplatin resistance, particularly with respect to its very low mutagenicity and different mode of action compared to platinum antitumor drugs in clinical use. Show less

We have synthesized and evaluated the biological properties of a compound of the type [η(6)-p-cymene)Ru(EtATSC)Cl]Cl (1) where EtATSC = 2-anthracen-9-ylmethylene-N-ethylhydrazinecarbothioamide, a thiosemicarbazone. The complex has been characterized by elemental analysis, spectroscopically (NMR, UV-Vis, and IR) and structurally by XRD. The in vitro anticancer activity of 1 has been evaluated against two human colon cancer cell lines. The IC(50) value for activity against HCT-116 was 224 ± 7 μM and 205 ± 5 μM against the Caco-2 cell line. The proficiency of 1 as an antibacterial agent was also evaluated against six bacterial strains. The minimum inhibitory concentration for Bacillus cereus was determined to be 5 μM and for Enterococcus faecalis it was 20 μM. At the maximum concentration tested the complex showed no activity against the Gram-negative strains. The complex binds strongly to human serum albumin with a binding constant of 1.37 ± 0.02 M(-1) at 308 K on a single binding site. It is also a strong binder to DNA with an apparent binding constant of 2.82 × 10(5) M(-1) at 308 K. 1 shows very good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 μM. Show less

This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X-ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl(2)NO(BPA)]is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis. Show less

The Ru(II) complex fac-[RuCl(dmso-S)(3)(dmso-O)(2)][PF(6)] (P2) was found to be an excellent precursor for the facile preparation in high yield of half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N)(2)][PF(6)] (e.g. (N)(2) = 1,2-diaminoethane (en, 4), trans-1,2-diaminocyclohexane (dach, 5), or 2 NH(3) (6)). Neutral half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N-O)] where N-O is an anionic chelating ligand (e.g. N-O = picolinate (pic, 7)) are best prepared from the universal Ru(II)-dmso precursor cis-[RuCl(2)(dmso)(4)] (P1). These complexes, that were fully characterized in solution and in the solid state, are structurally similar to the anticancer organometallic compounds [Ru(η(6)-arene)(chel)Cl][PF(6)](n) but, in place of a face-capping arene, have the fac-Ru(dmso-S)(3) fragment. In contrast to what observed for the corresponding arene compounds, that rapidly hydrolyze the Cl ligand upon dissolution in water, compounds 4-6 are very stable and inert in aqueous solution. Probably their inertness is the reason why they showed no significant cytotoxicity against the MDA-MB-231 cancer cell line. Show less

The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra. Show less

Bifunctional neutral half-sandwich Ru^II complexes of the type [(η⁶-arene)Ru(NH₃)Cl₂] where arene is p-cym (1) or bip (2) were synthesised by the reaction of N,N-dimethylbenzylamine (dmba), NH₄PF₆ and the corresponding Ru^II arene dimer, and were fully characterised. X-ray crystallographic studies of [(η⁶-p-cym)Ru(NH₃)Cl₂]·{(dmba-H)(PF₆)} (1a) and [(η⁶-bip)Ru(NH₃)Cl₂] (2) show extensive H-bond interactions in the solid state, mainly involving the NH₃ and the Cl ligands, as well as weak aromatic stacking interactions. The half-lives for the sequential hydrolysis of 1 and 2 determined by UV/Vis spectroscopy at 310 K ranged from a few minutes for the first aquation to ca. 45 min for the second aquation; the diaqua adducts were the predominant species at equilibrium. Arene loss during the aquation of complex 2 was observed. Upon hydrolysis, both complexes readily formed mono- and di-9-ethylguanine (9-EtG) adducts in aqueous solution at 310 K. The reaction reached equilibrium after ca. 1.8 h in the case of complex 1 and was slower but more complete for complex 2 (before the onset of arene loss at ca. 2.7 h). Complexes 1 and 2 were not cytotoxic towards A2780 human ovarian cancer cells up to the maximum concentration tested (100 μM). Show less

The low-spin 5d(6) Ir(III) organometallic half-sandwich complexes [(η(5)-Cp(x))Ir(XY)Cl](0/+), Cp(x) = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp(xph)), or tetramethyl(biphenyl)cyclopentadienyl (Cp(xbiph)), XY = 1,10-phenanthroline (4-6), 2,2'-bipyridine (7-9), ethylenediamine (10 and 11), or picolinate (12-14), hydrolyze rapidly. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; picolinate complexes bind to both purines. Cytotoxic potency toward A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cp(xbiph) > Cp(xph) > Cp*; Cp(xbiph) complexes 6 and 9 have submicromolar activity. Guanine residues are preferential binding sites for 4-6 on plasmid DNA. Hydrophobicity (log P), cell and nucleus accumulation of Ir correlate with cytotoxicity, 6 > 5 > 4; they distribute similarly within cells. The ability to displace DNA intercalator ethidium bromide from DNA correlates with cytotoxicity and viscosity of Ir-DNA adducts. The hydrophobicity and intercalative ability of Cp(xph) and Cp(xbiph) make a major contribution to the anticancer potency of their Ir(III) complexes. Show less

Replacing the N,N-chelating ligand 2,2'-bipyridine (bpy) in the Ir(III) pentamethylcyclopentadienyl (Cp*) complex [(η(5)-C(5)Me(5))Ir(bpy)Cl](+) (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(η(5)-C(5)Me(5))Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC(50) values of >100 μM for 1 and 10.8 μM for 2). Ir-Cl hydrolysis is rapid for both complexes (hydrolysis equilibrium reached in <5 min at 278 K). Complex 2 forms adducts with both 9-ethylguanine (9-EtG) and 9-methyladenine (9-MeA), but preferentially with 9-EtG when in competition (ca. 85% of total Ir after 24 h). The X-ray crystal structure of [(η(5)-C(5)Me(5))Ir(phpy)(9-EtG-N7)]NO(3)·1.5CH(2)Cl(2) confirms N7 binding to guanine. Two-dimensional NMR spectra show that complex 2 binds to adenine mainly through N1, consistent with density functional theory (DFT) calculations. DFT calculations indicate an interaction between the nitrogen of the NH(2) group (9-MeA) and carbons from phpy in the adenine adduct of complex 2. Calculations show that the most stable geometry of the adduct [(η(5)-C(5)Me(5))Ir(phpy)(9-EtG-N7)](+) (3b) has the C6O of 9-EtG orientated toward the pyridine ring of phpy, and for [(η(5)-C(5)Me(5))Ir(phpy)(9-MeA-N1)](+) (4(N1)a), the NH(2) group of 9-EtA is adjacent to the phenyl ring side of phpy. Complex 2 is more hydrophobic than complex 1, with log P values of 1.57 and -0.95, respectively. The strong nucleobase binding and high hydrophobicity of complex 2 probably contribute to its promising anticancer activity. Show less

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(η(6)-arene)(phenylazopyridine)X](+) in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF(3), OH or NO(2)). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(η(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(η(6)-bip)(3-Cl-azpy)I]PF(6) (23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs. 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

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

Four ruthenium(II) complexes with the formula [Ru(η(5)-C(5)H(5))(PP)L][CF(3)SO(3)], being (PP = two triphenylphosphine molecules), L = 1-benzylimidazole, ; (PP = two triphenylphosphine molecules), L = 2,2'bipyridine, ; (PP = two triphenylphosphine molecules), L = 4-Methylpyridine, ; (PP = 1,2-bis(diphenylphosphine)ethane), L = 4-Methylpyridine, , were prepared, in view to evaluate their potentialities as antitumor agents. The compounds were completely characterized by NMR spectroscopy and their crystal and molecular structures were determined by X-ray diffraction. Electrochemical studies were carried out giving for all the compounds quasi-reversible processes. The images obtained by atomic force microscopy (AFM) suggest interaction with pBR322 plasmid DNA. Measurements of the viscosity of solutions of free DNA and DNA incubated with different concentrations of the compounds confirmed this interaction. The cytotoxicity of compounds 1234 was much higher than that of cisplatin against human leukemia cancer cells (HL-60 cells). IC(50) values for all the compounds are in the range of submicromolar amounts. Apoptotic death percentage was also studied resulting similar than that of cisplatin. Show less

The synthesis of new modified indolo[3,2-c]quinoline ligands L(1)-L(8) with metal-binding sites is reported. By coordination to ruthenium- and osmium-arene moieties 16 complexes of the type [(η(6)-p-cymene)M(L)Cl]Cl (1a,b-8a,b), where M is Ru(II) or Os(II) and L is L(1)-L(8), have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV-vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (2a, 4a, 4b, 5a, 7a, and 7b). The complexes were tested for antiproliferative activity in vitro in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung cancer), yielding IC(50) values in the submicromolar or low micromolar range. Show less

Synthesis, structure and properties of two new flavanone complexes of Ru(ii) are described. The new complexes form during the reaction of ruthenium(iii) chloride with 3-aminoflavone (3-af) dissolved in an aliphatic alcohol. The formed products depend on the alcohol used and were found to be: cis-dichloridobis(3-imino-2-methoxyflavanone)ruthenium(ii)·3H(2)O (1) from a methanolic solution and cis-dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(ii)·2H(2)O (2) from an ethanolic solution, in which the original ligand 3-af had been converted by dehydrogenative alcoholysis to an entirely new ligand. This paper presents the X-ray structure and detailed (1)H-NMR analysis of both new compounds, as well as the study of their antiproliferative activity. The coordination of Ru(ii) is octahedral with [RuCl(2)N(2)O(2)] chromophores, having trans chlorides and common Ru-L distances. Both 1 and 2 are highly cytotoxic towards the cisplatin resistant EJ and L1210 cell lines, and both complexes are as active as cisplatin in the sensitive cell lines. They display the ability to overcome cisplatin resistance in the drug resistant sub-lines EJcisR and L1210R. The present evidence suggests that the mechanism of biological activity may be different for these ruthenium compounds compared to cisplatin. Show less

The synthesis, characterization, reactivity and in vitro anticancer activity of a series of Ru(II)-arene complexes with carbohydrate-derived phosphite and biscarboxylato co-ligands are reported. The compounds were characterized by NMR spectroscopy and electrospray ionization (ESI) mass spectrometry, and the molecular structures of oxalato(η(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-D-glucofuranoside)ruthenium(II) and oxalato(η(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-α-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. In contrast to their dichlorido counterparts, the biscarboxylato complexes did not exhibit significant reactivity towards biomolecules, such as cysteine, methionine, ubiquitin or the DNA model 5'-GMP, and resist hydrolysis; no hydrolytic species were detected by (1)H and (31)P{(1)H} NMR spectroscopy over several days. These structural alterations led to a decrease in the tumor-inhibiting potency of the compounds in human cancer cell lines. Show less

The intense luminescence of the new complex Ir(ppy)(2)(pybz) (1) within the cytoplasm of live cells can be discriminated from the fluorescence of an organic stain, solely on the basis of the emission timescale {pybzH = 2-pyridyl-benzimidazole}. The protonated form of 1 displays red-shifted emission, and may be implicated in a superior uptake compared to Ir(ppy)(3). Show less

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(I) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X = Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R = p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N'-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N'-chelating ligands for all Re(I) complexes. Biological activity of four oximine rhenium(I) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(I) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity. Show less

Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms. Show less