Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis,characterization and biological properties

(p-Cymene)-ruthenium bioconjugates ML (1) and ML₂ (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2_pG, 2_pA, 2_mG and 2_mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC₅₀ values of 5–30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV–Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC₅₀ values show higher binding affinities towards BSA. Compound 2_mG with value of IC₅₀ 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2_mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2_mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2_mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2_pG, 2_pA, 2_mG and 2_mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.     

Synthesis and biological evaluation of some new N(4)-substituted isatin-3-thiosemicarbazones

A new series of 12 N(4)-substituted isatin-3-thiosemicarbazones 2a-l has been synthesized, characterized and screened for in vitro cytotoxic, phytotoxic and urease inhibitory effects. All the compounds proved to be active in the brine shrimp bioassay; 2a, 2b, 2d, 2f and 2h-l exhibited a high degree of cytotoxic activity (LD(50) = 1.10 x 10(- 5) M-3.10 x 10(- 5) M). In urease-inhibition assay, compounds 2a, 2b, 2e, 2f, 2h-j and 2l proved to be potent inhibitors displaying relatively much greater inhibition of the enzyme with IC(50) values ranging from 20.6 microM to 50.6 microM. Amongst these, 2a and 2f were found to be the most potent ones exhibiting pronounced inhibition with IC(50) value 20.6 microM. All the synthetic compounds showed weak to moderate (10-40%) phytotoxicity at the highest tested concentration (500 microg/mL) indicating their usefulness as inhibitors of soil ureases.     

Synthesis,crystal structure and biological evaluation of a main group seven-coordinated bismuth(III) complex with 2-acetylpyridine N4-phenylthiosemicarbazone

Up to now, bismuth(III) complexes with thiosemicarbazones have been comparatively rare. Here, a main group seven-coordinated bismuth(III) complex [Bi(L)(NO₃)₂(CH₃CH₂OH)] (1) (HL = 2-acetylpyridine N(4)-phenylthiosemicarbazone) has been synthesized and characterized by elemental analysis, IR, ¹H NMR and single-crystal X-ray diffraction studies. The cytotoxicity data suggest that 1 exhibits higher in vitro antiproliferative activity in four human cancer cells tested. Its possible apoptotic mechanism has been evaluated in HepG2 cells. Compound 1 promotes a dose-dependent apoptosis in HepG2 cells and the apoptosis is associated with an increase in intracellular reactive oxygen species (ROS) production and reduction of mitochondrial membrane potential (MMP).     

Crystal structure of bis(pyrrole-N-carbothioate)bis(triphenylphosphine)nickel(II), C46H38N2S2P2Ni

The crystal structure of Ni(C₄H₄NCOS)₂[(C₆H₅)₃P]₂, Ni(ptc)₂(Ph₃P)₂, has been determined by single crystal X-ray diffraction methods. This species exists as a square planar complex. The structure is monoclinic, P2₁/n, a=12.759(4), b=10.069(2), c= 16.158(6) Å, and β=91.96(3)°. The unit cell contains 2 formula units with an observed density of 1.31 g cm⁻³ (1.34 calculated). The final R index= 0.047 (R_w=0.038) for 2618 non-zero reflections having I > 3 σ(I).     

Synthesis and biological evaluation of furopyrimidine N,O-nucleosides

A series of modified N,O-nucleosides, characterized by the presence of a furopyrimidine moiety, has been synthesized by exploiting a Sonogashira cross coupling reaction of 1-isoxazolidinyl-5-iodouracil with alkynes, followed by treatment with CuI in refluxing TEA/MeOH mixture. The obtained compounds were screened against both RNA and DNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. However, some of them were able to inhibit proliferation of MRC-5, Vero, BS-C-1 cells by 50% (CC₅₀) at concentrations ranging from 0.7 to 62.5 mM.     

Eight-coordination. Synthesis and structure of the schiff-base chelate bis(N,N′-disalicylidene-1,2-phenylenediamino)cerium(IV)

In an effort to elucidate the factors that determine the geometry of eight-coordinate complexes we synthesized and structurally characterizes the complex bis(N,N′-disalicylidene-1,2-phenylenediamino)Cerium(IV), Ce(salophen)₂. It is a square antiprismatic species with each chelating ligand spanning sss edges. The CeO bonds average 2.214 Å, appreciably shorter than CeN distance of 2.606 Å. The tow ligands have the sandwich orientation and the trapezoidal planes intersect at 88.2°. The δ angles are 7.0°, 2.6°, 56.5° and 55.9° and the ? angles are 30.0° and 28.6°. The complex crystallized in space group P2₁/C with Z = 4, a = 11.090(2) Å, b = 16.332(3) Å, c = 18.916(3) Å, β = 70.10(2)° and d_calc = 1.585 g/cm₃.     

Synthesis, characterization and electrochemistry of bis(3-aryl-6,6-dimethylcyclohexadienyl)ruthenium complexes

Five bis(3-aryl-6,6-dimethylcyclohexadienyl)ruthenium complexes (4a-4e) are prepared by reactions between di-μ-chlorodichlorobis[(1-3η:6-8η)-2,7-dimethyl-octadienyl]diruthenium and the corresponding dienes. The larger aryl substituents increase the barrier to rotation in 4a-4e relative to bis(3-methyl-6,6-cyclohexadienyl)ruthenium (5b). The activation parameters were determined by line-shape analysis for the exchange process in 4a: ΔG^† (183 K), 8.0 ± 0.2 kcal/mol; ΔH^†, 10.3 kcal/mol; and ΔS^†, 13 cal/mol/K. The electronic effect of the aryl substituents on the cyclohexadienyl ligand on the oxidation potential of the complex are compared to the effect of methyl substituents.     

Preparation, characterization, and catalytic properties of (triphenylphosphine)ruthenium complexes bearing N,O,N′-tridentate ligands

Preparation and characterization of (triphenylphosphine)ruthenium complexes bearing N,O,N′-tridentate ligands, [(L₁)RuCl(PPh₃)₂](BF₄) (L₁ = 2-[(2-pyridylmethoxy)methyl]pyridine), 1), [(L₂)RuCl(PPh₃)₂](BF₄) (L₂ = 8-(2-pyridylmethoxy)quinoline, 2) and [(L₃)RuCl₂(PPh₃)] (L₃ = 2-[(2-pyridylmethoxy)methyl]quinoline, 3) are described. Complexes 1-3 have been characterized by NMR and elemental analyses. Molecular structures of 2 and 3 have been determined by X-ray crystallography. Both compounds exhibit the octahedral geometry. L₂ adopts the facial configuration in 2 while L₃ is in a mer-arrangement in 3. Complexes 1-3 have proven to be able to catalyze the transfer hydrogenation of several ketones to alcohols in the presence of KOH and 2-propanol at refluxing, among which complex 3 was found to be the most active.     

Synthesis, crystal structures, in vitro biological evaluation of zinc(II) and bismuth(III) complexes of 2-acetylpyrazine N(4)-phenylthiosemicarbazone

Two metal complexes formulated as [Zn(L)(2)](2)·H(2)O (1) and [Bi(L)(NO(3))(2)(CH(3)OH)] (2), where HL=2-acetylpyrazine N(4)-phenylthiosemicarbazone, have been synthesized and characterized by elemental analysis, IR, MS, NMR and single-crystal X-ray diffraction studies. Biological studies, carried out in vitro against selected bacteria and the K562 leukemia cell lines, respectively, have shown that the free ligand and its two complexes may be endowed with important biological properties, especially HL with MIC=3.90 μg/mL against Pseudomonas aeruginosa, the zinc(II) complex 1 with IC(50)=1.0 μM against K562 leukemia cell lines, respectively. The compounds HL and 1 may exert their cytotoxicity activity via induced loss of mitochondria membrane potential (MMP).     

Synthesis and biological evaluation of diastereoisomerically pure N,O-nucleosides

Several N,O-nucleosides have been synthesized in good yields by direct 1,3-dipolar cyclization methodology, in the absence of solvent. A remarkable cis stereoselectivity (de 98%) was observed by tuning the substituents on the nitrone moiety. A good number of these N,O-nucleosides have been evaluated for cytotoxic activity against selected cellular lines. Some of the tested compounds have proven to be potential antiproliferative drugs.     

Dinuclear bis(terpyridine)ruthenium(II) complexes by amide coupling of ruthenium amino acids: Synthesis and properties

Two redox-asymmetric amide-bridged bis(terpyridine)ruthenium(II) complexes (3a, 3b) have been prepared by amide coupling of a carboxylic acid functionalized complex with an amine substituted complex and they were fully characterized by spectroscopic analyses. They emit at 692 and 750 nm at room temperature in fluid solution with quantum yields larger than 10⁻³ and ³MLCT lifetimes of 22 ns. Ru···Ru distances were estimated from DFT models as 17.7 and 13.4 Å for 3a and 3b, respectively. Cyclic voltammetry gives two oxidation potentials for the differently substituted ruthenium sites with splittings of 0.10 and 0.23 V for 3a and 3b, respectively. Oxidation of 3b with Ce^IV ions gives the corresponding mixed-valent Ru^II-Ru^III system which is valence-localized according to NIR spectroscopic and theoretical analyses.     

Synthesis,structure and electrochemistry of (ferrocene-2-propenoato-O,O′)bis[1,2-bis(diphenylphosphino)ethane-P,P′]ruthenium(II) hexafluorophosphate

The complex [Ru(η²-fcpe)(dppe)₂](PF₆) (1), where fcpe = ferrocene-2-propenoate and dppe = 1,2-bis(diphenylphosphino)ethane, was synthesized via a “dimer disassembly” method and characterized using elemental analysis, IR spectroscopy, ¹H and ³¹P NMR and X-ray crystallography. The redox potentials of the metal centers were assessed using cyclic voltammetry and Osteryoung square-wave voltammetry. No significant metal–metal interactions were found.     

Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones

A new series of 12 N⁴-substituted isatin-3-thiosemicarbazones 2a-l has been synthesized, characterized and screened for in vitro cytotoxic, phytotoxic and urease inhibitory effects. All the compounds proved to be active in the brine shrimp bioassay; 2a, 2b, 2d, 2f and 2h-l exhibited a high degree of cytotoxic activity (LD₅₀ = 1.10 × 10^{? 5} M–3.10 × 10^{? 5} M). In urease-inhibition assay, compounds 2a, 2b, 2e, 2f, 2h-j and 2l proved to be potent inhibitors displaying relatively much greater inhibition of the enzyme with IC₅₀ values ranging from 20.6 μM to 50.6 μM. Amongst these, 2a and 2f were found to be the most potent ones exhibiting pronounced inhibition with IC₅₀ value 20.6 μM. All the synthetic compounds showed weak to moderate (10–40%) phytotoxicity at the highest tested concentration (500 μg/mL) indicating their usefulness as inhibitors of soil ureases.     

Synthesis, characterization, structure, molecular modeling studies and biological activity of sterically crowded Pt(II) complexes containing bis(imidazole) ligands

The syntheses, structures and biological evaluation of a series of cisplatin-like complexes containing bis(imidazole) derivatives - the so-called Joseph ligands - are described. Their cytotoxicity is discussed in terms of their polar surface area, rate of aquation, and lipophilicity. The X-ray crystal structure of the platinum diiodido derivative of dimethyl 2-(di(1H-imidazol-2-yl)methyl)malonate) is reported and compared to those of related systems. Molecular modeling studies are focused on the hydrogen bonding properties of such systems, and their relevance to antitumor activity.     

Synthesis, characterization and crystal structure of dicesium bis(1,2-dithiole-3,5-dithiolato-4-yl)disulfide

Dicesium bis(1,2-dithiole-3,5-dithiolato-4-yl)disulfide, 3, was obtained by aerial oxidation of dicesium 1,3-dithiole-3-thione-4,5-dithiolate in aqueous ethanol. The dianion in 3, in the 4e special positions of the space group Pbcn, lies on a crystallographic twofold axis and has, therefore, C2 molecular symmetry. As a consequence the asymmetric unit consists of, in addition to one cesium atom, precisely one half of the anion. The negative charges of the dianion are sustained by 1,3-dithiolate groups. The cesium atom has 11 nearest sulfur atoms with CsS distances in the range 3.5762(11)-4.1383(11) Å, from five different anions and as a result provides complete three-dimensional connectivity throughout the structure. The vibrational spectra of 3 and related compounds, including dicesium 1,3-dithiole-3-thione-4,5-dithiolate are presented as are RHF calculations on [dmt]²⁻ and [dmt-dmt]²⁻ species.     

Synthesis, characterization, and antitumor properties of some metal complexes of 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones)

Complexes of Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones), abbreviated as H2L, have been prepared and characterized by elemental analysis, molar conductance, magnetic moments (300-78 K) and spectral studies. On the basis of these studies, a distorted six-coordinate structure for Fe(L)Cl and a distorted five-coordinate structure for M(L) (M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), or Pt(II] are suggested. The ligands undergo deprotonation and appear to coordinate through the thione sulphur, the imine nitrogen and pyridyl nitrogen. All the ligands and metal complexes were screened for their antitumor activity against P 388 lymphocytic leukemia test system in mice, and it was found that a few of them possess significant activity at the dosages used.     

Synthesis and characterization of ruthenium(II) complexes bearing the bis(2-pyridylmethyl)amine ligand

The reaction of [Ru(CO)₂Cl₂]_n with bis(2-pyridylmethyl)amine (bpma) in refluxing ethanol followed by anion exchange yields two products: cis,fac-[Ru(bpma)(CO)₂Cl]PF₆ (1a, 71%) and trans,fac-[Ru(bpma)(CO)₂Cl]PF₆ (1b, 29%). Reaction of 1a with AgBF₄ in acetone, followed by acetonitrile and then anion exchange gave cis,fac-[Ru(bpma)(CO)₂(CH₃CN)](PF₆)₂ (2a). In the same way, 1b afforded trans,fac-[Ru(bpma)(CO)₂(CH₃CN)](PF₆)₂ (2b). Reaction of depolymerized [Ru(CO)₂Cl₂]_n with bpma in ethanol at room temperature afforded cis,cis-[Ru(η²-bpma)(CO)₂Cl₂] (3). In refluxing ethanol, 3 was converted to cis,fac-[Ru(bpma)(CO)₂Cl]Cl (1a-Cl). Heating 3 in chlorobenzene afforded 1b-Cl, exclusively; heating 3 in ethylene glycol gave mainly 1a-Cl. Heating 1a-Cl in ethanol resulted in no isomerization, but heating in chlorobenzene gave a mixture of 3 and 1b-Cl. Anion exchange for PF₆ with 1a-Cl and 1b-Cl afforded 1a and 1b, respectively, whereas anion exchange for BPh₄ afforded 1a-BPh₄. Compounds 1a, 1b, 2a and 3 have been structurally characterized.     

Synthesis, antimicrobial and antioxidant evaluation of quinolines and bis(indolyl)methanes

An improved and practical synthesis of substituted quinolines and bis(indolyl)methanes was achieved under microwave condition using Zn(OTf)(2) as catalyst. The synthesized compounds have been screened for antimicrobial and antioxidant activities.     

Synthesis, interaction with double-helical DNA and biological activity of the water soluble complex cis-dichloro-1,2-propylenediamine-N,N,N',N'-tetraacetato ruthenium (III) (RAP)

The effects exerted by the new complex cis-dichloro-1,2-propylenediaminetetraacetato ruthenium (III), H[RuCl(2)(PDTA-H(2))] [1, RAP], on DNA and cultured tumor cells (ovarian carcinoma TG cell line) were studied. The comparative study of circular dichroism (CD) spectra obtained from DNA and RAP-DNA system evidences the interaction of the complex with DNA. Compound 1 also interacted with tumor TG cells to slow their proliferation rate. BrdU incorporation was enhanced in cells treated with compound 1, as evidenced by a single-cell electrophoresis method (comet assay), in accordance with RAP-induced DNA damage. DNA migration of compound 1-treated cells was similar to that induced by noxious agents other than cross-linking chemicals. The stability of [RuCl(2)(PDTA-H(2))]-DNA binding is suggested by the high degree of damage that persisted after removal of compound 1 from the culture medium.