The interaction of 5-fluoroorotic acid with transition metals: synthesis and characterisation of Ni(II), Cu(II) and Zn(II) complexes

5-Fluoroorotic acid (H(3)FOro) is a potent inhibitor for some metalloproteins such as dihydroorotase and dihydroorotate dehydrogenase and for thymidylate synthase (nonmetalloprotein) in the human malaria parasite Plasmodium falciparum. To study the coordination chemistry of H(3)Foro, the ammonium salt [NH(4)(+)][H(2)FOro(-)].1H(2)O (1) and the first coordination compounds of H(3)FOro with transition metals [Ni(HFOro(2-))(H(2)O)(4)].1H(2)O (2), [Cu(HFOro(2-))(NH(3))(H(2)O)](n) (3) and [Cu(3)(FOro(3-))(2)(NH(3))(6)(H(2)O)(2)] (4) have been synthesised and characterised by single-crystal X-ray diffraction, IR spectroscopy and by thermogravimetry. Three different coordination modes of 5-fluoroorotic acid have been established. In all cases the ligand is chelated to the metal via an amido-nitrogen and a carboxylate-oxygen but for (3), there is also a carboxylate oxygen from another HFOro(2-) ligand resulting in a polymeric structure and for (4), the second amido-nitrogen in the ororotic acid ring coordinates to give a trinuclear complex. The metal coordination polyhedra are octahedral in (2), square-pyramidal in (3) and square-planar and approximately square-pyramidal in (4). An octahedral coordination geometry including a N(1)/O(61)-chelating HFOro(2-) ligand with four aqua ligands is proposed for the Zn complex [Zn(HFOro(2-)) (H(2)O)(4)].0.5H(2)O (5), based on IR and thermogravimetric data. Extensive hydrogen bonded networks and some ring-ring stacking interactions are observed in each of the structures.     

Three new Cu(II) and Cd(II) complexes with 3-(2-pyridyl)pyrazole-based ligand: syntheses, crystal structures, and evaluations for bioactivities

Three new complexes [Cu(L)(2)(NO(3))](NO(3))(H(2)O)(1/2)(CH(3)OH)(1/2) (1), [Cd(L)(2)(NO(3))(2)](H(2)O)(3) (2) and [Cd(L)(2)(ClO(4))(CH(3)OH)](ClO(4))(H(2)O)(1/4)(CH(3)OH) (3) (L=1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene) were synthesized and characterized by elemental analyses, IR and X-ray diffraction analysis. Among them, the Cu(II) and Cd(II) ions were both coordinated by four N donors from two distinct L ligands via N,N-bidentate chelating coordination mode. Additional weak interactions, such as the face-to-face pi-pi stacking and C-Hcdots, three dots, centeredO H-bonding interactions, linked the mononuclear unit into 1D chain and further into 2D network. Complexes 1-3 were subjected to biological assays in vitro against six different cancer cell lines. All of them exhibited cytotoxic specificity and notable cancer cell inhibitory rate. The interactions of 1-3 with calf thymus DNA were investigated by thermal denaturation, viscosity measurements, spectrophotometric and electrophoresis methods. The results indicate that these complexes bound to DNA by intercalation mode via the ligand L and had different nuclease activities, which were in good agreement with their DNA-binding strength. Moreover, the central metal ions of 1-3 played a vital role in DNA-binding behaviors, DNA-cleavage activities and cytotoxicities, whereas the contribution of the different counter anions to their bioactivities also should not be ignored.     

Diazeniumdiolate reactivity in model membrane systems.

The effect of small unilamellar phospholipid vesicles on the acid-catalyzed dissociation of nitric oxide from diazeniumdiolate ions, R(1)R(2)N[N(O)NO](-), [1: R(1)=H(2)N(CH(2))(3)-, R(2)=H(2)N(CH(2))(3)NH(CH(2))(4)-; 2: R(1)=R(2)=H(2)N(CH(2))(3)-; 3: R(1)=n-butyl-, R(2)=n-butyl-NH2+(CH(2))(6)-; 4: R(1)=R(2)=nPr-] has been examined at pH 7.4 and 37 degrees C. NO release was catalyzed by anionic liposomes (DPPG, DOPG, DMPS, POPS and DOPA) and by mixed phosphatidylglycerol/phosphatidylcholine (DPPG/DPPC and DOPG/DPPC) covesicles, while cationic liposomes derived from 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic liposome DMPC did not significantly affect the dissociation rates of the substrates examined. Enhancement of the dissociation rate constant in DPPG liposome media (0.010M phosphate buffer, pH 7.4, 37 degrees C) at 10mM phosphoglycerol levels, ranged from 37 for 1 to 1.2 for the anionic diazeniumdiolate 4, while DOPA effected the greatest rate enhancement, achieving 49-fold rate increases with 1 under similar conditions. The observed catalysis decreases with increase in the bulk concentration of electrolytes in the reaction media. Quantitative analysis of catalytic effects has been obtained through the application of pseudo-phase kinetic models and equilibrium binding constants at different liposome interfaces are compared. The stoichiometry of nitric oxide release from 1 and 2 in DPPG/DPPC liposome media has been obtained through oxyhemoglobin assay. DPPG=1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], DOPG=1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], DMPS=1,2-dimyristoyl-sn-glycero-3-[phospho-l-serine], POPS=1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-l-serine], DOPA=1,2-dioleoyl-sn-glycero-3-phosphate; DPPC=1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DMPC=1,2-dimyristoyl-sn-glycero-3-phosphocholine, DOTAP=1,2-dioleoyl-3-trimethylammonium-propane.     

Unusual coordinating behavior by three non-steroidal anti-inflammatory drugs from the oxicam family towards copper(II). Synthesis, X-ray structure for copper(II)-isoxicam, -meloxicam and -cinnoxicam-derivative complexes, and cytotoxic activity for a copper(II)-piroxicam complex

Cytotoxic tests recently performed at National Cancer Institute, NCI (USA), on [Cu(HPIR)(2)(DMF)(2)], 1, (H(2)PIR=piroxicam, 4-hydroxy-2-methyl-N-pyridin-2-yl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) a widely used non-steroidal anti-inflammatory drug, NSAID [see R. Cini, G. Giorgi, A. Cinquantini, C. Rossi, M. Sabat, Inorg. Chem. 29 (1990) 5197-5200, for synthesis and structural characterization, DMF=dimethylformamide] (NSC #624662) by using a panel of ca. 50 human cancer cells, showed growth inhibition factor GI(50) values as low as 20microM against several cancer lines, with an average value 54.4microM. The activity of 1 is larger against ovarian cancer cells, non-small lung cancer cells, melanoma cancer cells, and central nervous system cancer cells. The widely used anticancer drug carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)) (NSC #241240) has average GI(50) value of 102microM. The reactions of copper(II)-acetate with other NSAIDs from the oxicam family were tested and crystalline complexes were obtained and characterized. Isoxicam (H(2)ISO=4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HISO)(2)].0.5DMF, 2.0.5DMF (DMF=dimethylfomamide). The coordination arrangement is square-planar and the HISO(-) anions behave as ambi-dentate chelators via O(amide),N(isoxazole) and O(enolate),O(amide) donors. Meloxicam (H(2)MEL=4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HMEL)(2)(DMF)].0.25H(2)O, 3.0.25H(2)O. The coordination arrangement is square-pyramidal, the equatorial donors being O(amide),N(thiazole) from two HMEL(-) anions and the apical donor being O(DMF). Unexpectedly, cinnoxicam (HCIN=2-methyl-1,1-dioxido-3-[(pyridin-2-ylamino)carbonyl]-2H-1,2-benzothiazin-4-yl-(3-phenylacrylate)) produced [Cu(MBT)(2)(PPA)(2)] (MBT=3-(methoxycarbonyl)-2-methyl-2H-1,2-benzothiazin-4-olate 1,1-dioxide, PPA=3-phenyl-N-pyridin-2-ylacrylamide).     

Synthesis, characterization, DNA-binding and cleavage studies of [Ru(bpy)2(actatp)]2+ and [Ru(phen)2(actatp)]2+ (actatp=acenaphthereno[1,2-b]-1,4,8,9-tetraazariphenylence)

New ligand acenaphthereno[1,2-b]-1,4,8,9-tetraazariphenylence (actatp) and its complexes [Ru(bpy)(2)(actatp)](ClO(4))(2).2H(2)O (1) (bpy=2,2'-bipyridine) and [Ru(phen)(2)(actatp)](ClO(4))(2).2H(2)O (2) (phen=1,10-phenanthroline) have been synthesized and characterized by UV-vis, 1H NMR, and mass spectra. The electrochemical behavior of the two complexes was studied by cyclic voltammetry. The interaction of the two complexes with calf thymus DNA has been investigated by spectrophotometric methods and viscosity measurements. The experimental results suggest that both complexes bind to DNA through an intercalative mode. The circular dichroism signals of the dialysates of the racemic complexes against calf thymus DNA are discussed. When irradiated at 302 nm, both complexes have also been found to promote the photocleavage of plasmid pBR 322 DNA.     

Interaction of purine nucleotides with inert paramagnetic Cr(III) probes evaluated by NMR relaxation effects. Molecular mechanics calculations on Cr(III) and Co(III) polyphosphate complexes

The 1H NMR relaxation effects produced by paramagnetic Cr(III) complexes on nucleoside 5'-mono- and -triphosphates in D2O solution at pH' = 3 were measured. The paramagnetic probes were [Cr(III)(H2O)6]3+, [Cr(III)(H2O)3(HATP)], [Cr(III)(H2O)3(HCTP)] and [Cr(III)(H2O)3(UTP)-, while the matrix nucleotides (0.1 M) were H2AMP, HIMP-, and H2ATP2-. For the aromatic base protons, the ratios of the transverse to longitudinal paramagnetic relaxation rates (R2p/R1p) for the [Cr(III)(H2O)6]3+/H2ATP2-, [Cr(III)(H2O)3(HATP)]/H2ATP2-, [Cr(III)(H2O)3(HCTP)]/H2ATP2 and [Cr(III)(H2O)3(UTP)]-/H2ATP2 systems were below 2.33 so the dipolar term predominates. For a given nucleotide, R1p for the purine H(8) signal was larger than for the H(2) signal with the [Cr(III)(H2O)6]3+ probe, while R1p for the H(2) signal was larger with all the other Cr(III) probes. Molecular mechanics computations on the [Cr(III)(H2O)4(HPP)(alpha,beta)], [Cr(III)(NH3)4(HPP)(alpha,beta)], [Co(III)(NH3)3(H2PPP)(alpha,beta,gamma)] and [Co(III)(NH3)4(HPP)(alpha,beta)] complexes gave calculated energy-minimized geometries in good agreement with those reported in crystal structures. The molecular mechanics force constants found were then used to calculate the geometry of the inner sphere [Cr(III)(H2O)6]3+ and [Cr(III)(H2O)3(HATP)(alpha,beta,gamma)] complexes as well as the structures of the outer sphere [Cr(III)(H2O)6]3(+)-(H2AMP) and [Cr(III)(H2O)6]-(HIMP)- species. The gas-phase structure of the [Cr(III)(H2O)3(HATP)(alpha,beta,gamma)] complex shows the existence of a hydrogen bond interaction between a water ligand and the adenine N(7)(O...N = 2.82 A). The structure is also stabilized by intramolecular hydrogen bonds involving the -O(2')H group and the adenine N(3) (O...N = 2.80 A) as well as phosphate oxygen atoms and a water molecule (O...O = 2.47 A). The metal center has an almost regular octahedral coordination geometry. The structures of the two outer-sphere species reveal that the phosphate group interacts strongly with the hexa-aquochromium probe. In both complexes, the nucleotides have a similar "anti" conformation around the N(9)-C(1') glycosidic bond. However, a very important difference characterizes the two structures. For the (HIMP)- complex, strong hydrogen bond interactions exist between one and two water ligands and the inosine N(7) and O(6) atoms, respectively (O...O = 2.63 A; O...N = 2.72, 2.70 A). For the H2AMP complex, the [Cr(III)(H2O)6]3+ cation does not interact with N(7) since it is far from the purine system. Hydrogen bonds occur between water ligands and phosphate oxygens. The Cr-H(8) and Cr-H(2) distances revealed by the energy-minimized geometries for the two outer sphere species were used to calculate the R1p values for the H(8) and H(2) signals for comparison with the observed R1p values: 0.92(c), 1.04(ob) (H(8)) and 0.06(c), 0.35(ob) (H(2)) for H2AMP; and 3.76(c), 4.53(ob) (H(8)) and 0.16(c), 0.77(ob) s-1 (H(2)) for HIMP-.(ABSTRACT TRUNCATED AT 400 WORDS)     

Uracilato and 5-halouracilato complexes of Cu(II), Zn(II) and Ni(II). X-ray structures of [Cu(uracilato-N(1))(2)(NH(3))(2)].2(H(2)O), [Cu(5-chlorouracilato-N(1))(2)(NH(3))(2)](H(2)O)(2), [Ni(5-chlorouracilato-N(1))(2)(en)(2)].2H(2)O and [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato-N(1)).(H(2)O)

Four new complexes of uracilato and 5-halouracilato with the divalent metal ions Cu(II), Zn(II) and Ni(II) were obtained and structurally characterized. [Cu(uracilato- N(1))(2)(NH(3))(2)].2(H(2)O) (1) and [Cu(5-chlorouracilato-N(1))(2)(NH(3))(2)](H(2)O)(2) (2) complexes present distorted square planar co-ordination geometry around the metal ion. Although an additional axial water molecule is present [Cu(II)-OH(2)=2.89 A (for 1) and 2.52 A (for 2)] in both cases, only in the complex 2 would be considered in the limit of a bond distance. The Zn(II) in [Zn(5-chlorouracilato-N(1))(NH(3))(3)].(5-chlorouracilato-N(1)).(H(2)O) presents a tetrahedral co-ordination with three ammonia molecules and the N(1) of the corresponding uracilato moiety. A non-coordinated uracilato molecule is present as a counterion and a recognition between co-ordinated and free ligands, by means a tandem of H-bonds, should be mentioned. Finally, the complex [Ni(5-chlorouracilato-N(1))(2)(en)(2)] (H(2)O)(2) (where en is ethylenediamine) presents a typical octahedral trans co-ordination with additional hydrogen bonds between 5-chlorouracilato and the NH(2) groups of ethylenediamine units.     

Guanine binding of a cytotoxic platinum-acridin-9-ylthiourea conjugate monitored by 1-D 1H and 2-D [1H,15N] NMR spectroscopy: hydrolysis is not the rate-determining step

The reaction of [PtCl(en)(ACRAMTU)](NO(3))(2) (PT-ACRAMTU, 1; ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, en=ethane-1,2-diamine) and the [(15)N]-en labeled analogue, 1', with 2'-deoxyguanosine (dG) was studied by (1)H NMR and two-dimensional [(1)H,(15)N] HSQC (heteronuclear single quantum coherence) spectroscopy. Reactions were performed in phosphate buffered solution at 37 degrees C at various ratios and total concentrations of reactants. The (1)H NMR data suggest that the hydrolyzed form of the drug, [Pt(H(2)O)(en)(ACRAMTU)](3+) (1a), forms at a rate (k(1)) similar to that observed in classical platinum chloroam(m)ines but to only a minor extent ( approximately 15%). Attempts to detect and characterize 1'a by two-dimensional NMR spectroscopy, however, were unsuccessful, and 1' and dG( *) were the only species observed in the HSQC spectra. Reaction of the putative aqua intermediate 1a with dG to yield [Pt(en)(dG-N7)(ACRAMTU)](3+) (dG( *)) is slow and is highly dependent on the initial concentrations of the reactants. This unusual observation is consistent with a mechanism in which a second-order term becomes rate-determining (k(2)相似文献   

Relatively stable N-ligated [2Fe2S](2+) clusters with dipyrromethane capping ligands

[2Fe2S] clusters with terminal N-ligation (His, Arg) and unique functions are increasingly recognized in biological systems. In this work three new [2Fe2S] clusters 1-3 with different 1,1'-dipyrrolmethane derivatives as chelating terminal ligands have been prepared and fully characterized, including by X-ray crystallography: (NEt(4))(2)[L(2)Fe(2)(mu-S)(2)] with L=Me(2)C(C(4)H(3)N)(2) (1), Ph(2)C(C(4)H(3)N)(2) (2), (CH(2))(5)C(C(4)H(3)N)(2) (3). These systems represent rare examples of synthetic [2Fe2S] complexes with N-donor capping ligands. While geometric parameters as well as spectroscopic and electrochemical characteristics of the new complexes are as anticipated, the chelating nature of the terminal ligands in 1-3 imparts a relatively high stability that will be advantageous for reactivity studies of the [2Fe2S] core.     

Oxidative strand scission of nucleic acids by a multinuclear copper(II) complex

The compound [Cu(2)(II)(D(1))(H(2)O)(2)](ClO(4))(4).2H(2)O [D(1)=binucleating ligand with tris(2-pyridylmethyl)amine (TMPA) moieties linked in the 5-pyridyl position by a -CH(2)CH(2)- bridge] mediated efficient oxidative cleavage of pBR322 plasmid DNA under reducing conditions. A mononuclear analogue, [Cu(TMPA)(H(2)O)](ClO(4))(2), was less effective at linearizing supercoiled (Form I) plasmid DNA as compared to the binuclear complex. A new method for quenching the copper-dependent reactions has been developed to avoid plasmid scission by the binuclear complex and the standard gel loading buffer. EDTA was not sufficient for retarding copper reaction, but diethyldithiocarbamic acid was capable of inhibiting all reactivity. Investigation of oxidative cleavage of double-helical oligonucleotides by [Cu(2)(II)(D(1))(H(2)O)(2)](ClO(4))(4) confirmed the enhanced reactivity of the binuclear over the mononuclear complex and provided mechanistic insights into the nature of the reaction. Cleavage of DNA required both the binuclear complex and a reductant and likely proceeded through an O(2)-derived intermediate that does not include a diffusible hydroxyl radical. The greater efficiency of the binuclear complex relative to the mononuclear analogue is consistent with their relative abilities to activate dioxygen.     

Single diastereomers of unsymmetrical tris-spirocyclic cyclotriphosphazenes based on 1,1'-bi-2-naphthol--synthesis and structures

Diastereoselective synthesis and characterization of chiral unsymmetrical tris-spirocyclic cyclotriphosphazenes based on chiral 1,1'-bi-2-naphthol (BINOL) are reported. Specifically, the chiral compounds (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)Cl(2) [(-)-4] and (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2)NMe)(2) [(-)-5] are prepared by starting with the chiral mono-spiro compound (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)]Cl(4) [(-)-3]. Synthesis of four other chiral spirocyclics, N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2) NMe)(O-2,2'C(6)H(4)-C(6)H(4)O)[(-)-6 and (+)-6], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](NMe(2))(4) [(-)-7], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)(NMeCH(2)CH(2)OH)(2) [(-)-8 and (+)-8], and N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)[NHCH(2)CH(2)CH(2)Si(OEt)(3)](2) (9) is also reported herein. Compounds 4-6 are obtained in the solid state diastereoselectively and their X-ray structures have been determined and discussed. The diastereoselectivity is also shown by structural characterization of two distinct isomers in the case of 6 [(-)-6 and (+)-6, respectively] by starting with precursor of 3 having (R) or (S)-BINOL residue. The (1)H NMR spectra of 7 and 8 exhibit doublets with virtual coupling for the methyl protons, consistent with the chiral nature of the binaphthoxy residue. The potential of 9, which hydrolyzes readily in CDCl(3) solution, as a useful precursor for chiral polymer applications is highlighted.     

Photogeneration of titanium(III) from titanium(IV) citrate in aqueous solution

Current interest in the biochemistry of Ti(IV) arises from its widespread use in white pigments and its potential in therapeutic agents. Citrate is known to form strong complexes with Ti(IV). We show here that Ti(III) citrate is generated in a facile manner and in good yield by the action of UV radiation on Ti(IV) citrate in aqueous solution. The Ti(III)-citrate species formed was isolated and characterised by UV-Visible spectroscopy, showing an absorption at 547 nm (epsilon=100 M(-1)cm(-1)), and by electron paramagnetic resonance (EPR) spectroscopy giving a resonance at g=1.949 (linewidth=60G) . An X-ray structure of the parent Ti(IV) complex in the form [TiNa(3)(C(6)H(6)O(7))(2)(C(6)H(5)O(7))(H(2)O)(6.8)].2H(2)O is reported along with a study of the reaction of Ti(IV)-citrate with N,N-ethylenebis(o-hydroxytoluene)glycine (EHTG), which was more rapid than those of other related Ti(IV) complexes.     

Synthesis, inhibitory activity and molecular docking studies of two Cu(II) complexes against Helicobacter pylori urease

Two mononuclear copper(II) complexes, [Cu(C(15)H(16)NO(2))(2)] (1) and [Cu(C(6)H(9)N(2)O(4))(2)·3H(2)O] (2·3H(2)O), were synthesised and structurally characterised by single-crystal X-ray analysis. The copper(II) atom adopts a square-planar environment in complex 1, while the geometry in 2·3H(2)O could be described as the distorted square pyramidal. Complexes 1 and 2·3H(2)O were evaluated for their inhibitory activities against Helicobacter pylori (H. pylori) urease in vitro. They both were found to have strong inhibitory activities against H. pylori urease comparable to that of acetohydroxamic acid (AHA). A docking simulation was performed to position 2 into the H. pylori urease active site to determine the probable binding conformation.     

Synthesis,crystal structure,and nuclease activity of planar mono-heterocyclic base copper(II) complexes

A series of mononuclear copper(II) complexes having a 1:1 molar ratio of copper and the planar heterocyclic base like 1,10-phenanthroline (phen), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) and dipyrido[3,2-a:2',3'-c]phenazine (dppz) are prepared from a reaction of copper(II) nitrate.trihydrate and the base (L) in ethanol or aqueous ethanol at different temperatures. The complexes [Cu(dpq)(NO(3))(2)] (2), [Cu(dpq)(NO(3))(H(2)O)(2)](NO(3)) (3), [Cu(dpq)(NO(3))(2)(H(2)O)(2)].2H(2)O (4.2H(2)O) and [Cu(dppz)(NO(3))(2)(H(2)O)].H(2)O (5.H(2)O) have been characterized by X-ray crystallography. The crystal structures show the presence of the heterocyclic base in the basal plane. The coordination geometries of the copper(II) centers are axially elongated square-pyramidal (4+1) in 2, 3 and 5, and octahedral (4+2) in 4. The nitrate anion in the coordination sphere displays unidentate and bidentate chelating bonding modes. The axial ligand is either H(2)O or NO(3) in these structures giving a Cu-L(ax) distance of approximately 2.4 A. The one-electron paramagnetic complexes (mu approximately 1.8 mu(B)) exhibit axial EPR spectra in DMF glass at 77 K giving g(parallel)>g( perpendicular ) with an A(parallel) value of approximately 170G indicating a [d(x)2(-y)2](1) ground state. The complexes are redox active and display a quasireversible cyclic voltammetric response for the Cu(II)/Cu(I) couple near 0.0 V vs. SCE giving an order of the E(1/2) values as 5(dppz)>2-4 (dpq)>[Cu(phen)(2)(H(2)O)](2+)>1 (phen). The complexes bind to calf thymus DNA giving an order 5 (dppz)>2 (dpq)>[Cu(phen)(2)(H(2)O)](2+)>1 (phen). An effect of the extended planar ring in dpq and dppz is observed in the DNA binding. The complexes show nuclease activity with pUC19 supercoiled DNA in DMF/Tris-HCl buffer containing NaCl in presence of mercaptopropanoic acid as a reducing agent. The extent of cleavage follows the order: [Cu(phen)(2)(H(2)O)](ClO(4))(2)>5>2 approximately 3 approximately 4>1. The bis-phen complex is a better cleaver of SC DNA than 1-5 having mono-heterocyclic base. Mechanistic investigations using distamycin reveal minor groove biding for the phen, dpq complexes, and a major groove binding for the dppz complex 5. The cleavage reactions are found to be inhibited in the presence of hydroxyl radical scavenger DMSO and the reactions are proposed to proceed via sugar hydrogen abstraction pathway. The ancillary ligand is found to have less effect in DNA binding but are of importance in DNA cleavage reactions.     

The influence of methionine-containing peptides on the reaction of carboplatin with 5'-guanosine monophosphate: a comparison with cisplatin

The pH- and time-dependent reaction of the anticancer drug carboplatin, [Pt(cbdca-kappa(2)O,O')(NH(3))(2)] (cbdca=cyclobutane-1,1-dicarboxylate), with the tripeptides H-glyglymet-OH (glycylglycyl-L-methionine) and Ac-glyglymet-OH at 313 K was investigated by high-performance liquid chromatography, NMR and mass spectrometry. The relative stability of the initial ring-opened kappaS complex [Pt(cbdca-kappaO)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] leads to increased formation of the kinetically favoured kappaS:kappaS' bis-adduct [Pt(Ac-glyglymet-OH-kappaS)(2)(NH(3))(2)](2+) in comparison with cisplatin. As a result a second 1:2 reaction pathway kappaS-->kappaS:kappaS'-->kappa(2)N(M), S:kappaS'-->kappa(3)N(G2),N(M), S:kappaS', where N(M) and N(G2) represent, respectively, metallated methionine and glycine nitrogen atoms, competes with the 1:1 route kappaS-->kappa(2)N(M), S-->kappa(3)N(G2),N(M), S also observed for cisplatin. Cleavage of N-acetylglycine at the backbone C(O)-N bond to the second gly residue (G2) is observed after 100 h for the respective tridentate complexes [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S) (Ac-glyglymet-OH-kappaS)] and [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S)(NH(3))] at pH <5.2. The longevity of the initial kappaS complex leads to about an eight-fold increase in the rate of formation of the kappaN7:kappaN7' bis-adduct [Pt(5'-GMP-kappaN7)(2)(NH(3))(2)](2-) for the reaction of carboplatin with 5'-GMP(2-) at pH 7 in the presence of Ac-glyglymet-OH. A mixed-ligand kappaS:kappaN7 species [Pt(5'-GMP-kappaN7)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] provides the major precursor for this 1:2 nucleotide complex and kappaN7 coordination of 5'-GMP(2-) is also observed in the kappa(2)N(M),S:kappaN7 complex [Pt(5'-GMP-kappaN7)(Ac-glyglymetH(-1)-OH-kappa(2)N(M),S)(NH(3))(2)](-) formed by substitution of the ammine ligand trans to the methionine sulphur. As the intermediate kappaS:kappaN7 species is formed rapidly within the first 10 h of reaction, these results suggest that the transfer reaction pathway kappaS-->kappaS:kappaN7-->kappaN7:kappaN7' involving kappaS platinated peptides could play an important role in accelerating the rate of DNA binding for carboplatin.     

trans-[Ru(NO)(NH3)4(py)](BF4)3.H2O encapsulated in PLGA microparticles for delivery of nitric oxide to B16-F10 cells: Cytotoxicity and phototoxicity

The NO donor trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O (py=pyridine) was loaded into poly-lactic-co-glycolic acid (PLGA) microparticles using the double emulsification technique. Scanning electron microscopy (SEM) and dynamic light scattering revealed that the particles are spherical in shape, have a diameter of 1600nm, and have low tendency to aggregate. The entrapment efficiency was 25%. SEM analysis of the melanoma cell B16-F10 in the presence of the microparticles containing the complex trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O (pyMP) showed that the microparticles were adhered to the cell surface after 2h of incubation. The complex with concentrations lower than 1x10(-4)M did not show toxicity in B16-F10 murine cells. The complex in solution is toxic at higher concentrations (>1x10(-3)M), with cell death attributed to NO release following the reduction of the complex. pyMP is not cytotoxic due to the lower bioavailability and availability of the entrapped complex to the medium and its reducing agents. However, pyMP is phototoxic upon light irradiation. The phototoxicity strongly suggests that cell death is due to NO release from trans-[Ru(NO)(NH(3))(4)(py)](3+). This work shows that pyMP can serve as a model for a drug delivery system carrying the NO donor trans-[Ru(NO)(NH(3))(4)(py)](BF(4))(3).H(2)O, which can release NO locally at the tumor cell by irradiation with light only.     

Synthesis,structural characterization and antimicrobial activities of 12 zinc(II) complexes with four thiosemicarbazone and two semicarbazone ligands

Twelve zinc(II) complexes with thiosemicarbazone and semicarbazone ligands were prepared and characterized by elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FT-IR and 1H and 13C NMR spectroscopy. Seven three-dimensional structures of zinc(II) complexes were determined by single-crystal X-ray analysis. Their antimicrobial activities were evaluated by MIC against four bacteria (B. subtilis, S. aureus, E. coli and P. aeruginosa), two yeasts (C. albicans and S. cerevisiae) and two molds (A. niger and P. citrinum). The 5- and 6-coordinate zinc(II) complexes with a tridentate thiosemicarbazone ligand (Hatsc), ([Zn(atsc)(OAc)](n) 1, [Zn(Hatsc)(2)](NO(3))(2).0.3H(2)O 2, [ZnCl(2)(Hatsc)] 3 and [Zn(SO(4))(Hatsc)(H(2)O)].H(2)O 4 [Hatsc=2-acetylpyridine(thiosemicarbazone)]), showed antimicrobial activities against test organisms, which were different from those of free ligands or the starting zinc(II) compounds. Especially, complex 2 showed effective activities against P. aeruginosa, C. albicans and moderate activities against S. cerevisiae and two molds. These facts are in contrast to the results that the 5- or 6-coordinate zinc(II) complexes with a tridentate 2-acetylpyridine-4N-morpholinethiosemicarbazone, ([Zn(mtsc)(2)].0.2EtOH 5, the previously reported catena-poly [Zn(mtsc)-mu-(OAc-O,O')](n) and [Zn(NO(3))(2)(Hmtsc)] [Hmtsc=2-acetylpyridine (4N-morpholyl thiosemicarbazone)]), showed no activities against the test microorganisms. The 5- and 6-coordinate zinc(II) complexes with a tridentate 2-acetylpyridinesemicarbazone, ([Zn(OAc)(2)(Hasc)] 6 and [Zn(Hasc)(2)](NO(3))(2) 7 [Hasc=2-acetylpyridine(semicarbazone)]), showed no antimicrobial activities against bacteria, yeasts and molds. Complex [ZnCl(2)(Hasc)] 8, which was isostructural to complex 3, showed modest activity against Gram-positive bacterium, B. subtilis. The 1:1 complexes of zinc(II) with pentadentate thiosemicarbazone ligands, ([Zn(dmtsc)](n) 9 and [Zn(datsc)](n) 10 [H(2)dmtsc=2,6-diacetylpyridine bis(4N-morpholyl thiosemicarbazone) and H(2)datsc=2,6-diacetylpyridine bis(thiosemicarbazone)]), did not inhibit the growth of the test organisms. On the contrary, 7-coordinate zinc(II) complexes with one pentadentate semicarbazone ligand and two water molecules, ([Zn(H(2)dasc)(H(2)O)(2)](OAc)(2).5.3H(2)O 11 and [Zn(H(2)dasc)(H(2)O)(2)](NO(3))(2).H(2)O 12 [H(2)dasc=2,6-diacetylpyridine bis(semicarbazone)]), showed modest to moderate activities against bacteria. Based on the X-ray structures, the structure-activity correlation for the antimicrobial activities was elucidated. The zinc(II) complexes with 4N-substituted ligands showed no antimicrobial activities. In contrast to the previously reported nickel(II) complexes, properties of the ligands such as the ability to form hydrogen bonding with a counter anion or hydrated water molecules or the less bulkiness of the 4N moiety would be a more important factor for antimicrobial activities than the coordination number of the metal ion for the zinc(II) complexes.     

Au(2)(micro-G)(micro-dmpe)].(KBr)(0.75) 2H(2)O, a cyclic dinuclear gold(I) complex with an N3,N9-bridging coordination mode of guanine and aurophilic interactions: synthesis, X-ray crystal structure and luminescence properties (dmpe=1,2-bis(dimethylphosphino)ethane and G=guaninato dianion)

The digold complex [Au(2)(micro-G)(micro-dmpe)](KBr)(0.75) x 2H(2)O (dmpe=1,2-bis(dimethylphosphino)ethane (1)) has been prepared by nucleophilic attack of the guaninate dianion on the gold(I) atoms of [(AuBr)(2)(micro-dmpe)] and has been characterised by X-ray crystallography and spectroscopic studies. The structure of 1 consists of dinuclear nine-membered ring molecules, K(+) cations, Br(-) anions and water molecules, all of them involved in either weak K....O or hydrogen bonding interactions. Within the cyclic dinuclear molecules, gold(I) atoms are bridged on one side by the diphosphine ligand and on the other side by a doubly deprotonated guaninate anion coordinated through neighbouring N3 and N9 nitrogen atoms, with gold(I)....gold(I) interactions of 3.030(2) A. This is the first X-ray example showing an N3,N9-bridging mode for guanine. There are two types of K(+) cations in the structure, K1 and K2. The former interacts with water molecules to form a unique [K(H(2)O)(3)(micro-H(2)O)(2)K(H(2)O)(3)](2+) dipotassium unit whereas K2 interact with the O6 atom of the guaninate ligands and oxygen atoms of the dipotassium unit leading to a chain running along the c-axis. Each chain is interdigitated with four neighbouring ones to give rise to an intricate network in which Br1, Br2 and [K(H(2)O)(3)(micro-H(2)O)(2)K(H(2)O)(3)](2+) fit snugly into cavities defined by digold molecules. Complex 1 luminescence at room temperature and 77 K in the solid state with excitation maxima at 385 nm and emission maxima at 451.8 and 448.7 nm, respectively. The emission spectrum of a saturated solution of 1 in DMSO (dimethyl sulfoxide) shows the maximum at about 440 nm.     

Syntheses,characterization and X-ray structures of the fac-[RuCl3(NO)(dppe)] and the trans-[RuCl(NO)(dppe)2]2+ species

Trans-[RuCl(NO)(dppe)2]2+ species were prepared. The complexes have been characterized by microanalysis, IR and 31P[1H] NMR spectroscopy and cyclic voltammetry. The trans-[RuCl(NO)(dppe)2](ClO4)2 complex shows a reversible one-electron-reduction process at E(1/2) = 0.200 V and another one-electron-reduction irreversible process at -0.620 V, both centered at the NO+ group. The dissociation of the NO group from the trans-[RuCl(NO)(dppe)2]2+ after two one-electron reductions results in the formation of the trans- and cis-[RuCl2(dppe)2] isomers. The product of an electrolyzed solution of the same complex at -0.300 V shows an EPR signal consistent with the presence of the [RuCl(NO(0))(dppe)2]+ complex. Crystal data for trans-[RuCl(NO)(dppe)2]2+*[RuCl4(NO)(H2O)]*1/2[RuCl6]4-*2[H2O] (I) and trans-[RuCl(NO)(dppe)(2)]2+*2[RuCl4(NO)(CH3O)]-*3[CH3OH] (II) are as follow: (I) Space group P-1, a=10.4040(3) A, b=12.3470(4) A, c=23.5620(8) A, alpha=95.885(2) degrees, beta=99.608(2) degrees, gamma=104.378(2) degrees, R=0.0521; (II) space group P-1, a=10.9769(2) A, b=13.2753(3) A, c=24.0287(4) A, alpha=99.743(1) degrees, beta=95.847(1) degrees, gamma=97.549(1) degrees; R=0.0496. The fac-[RuCl3(NO)(dppe)] (III) complex has been also prepared; its crystal data are: space group P2(1)/n (No. 14), a=11.841(2) A, b=13.775(2) A, c=16.295(4) A, beta=92.81(2) degrees; R1=0.0395.     

Synthesis, characterisation and antimicrobial activity of copper(II) and manganese(II) complexes of coumarin-6,7-dioxyacetic acid (cdoaH2) and 4-methylcoumarin-6,7-dioxyacetic acid (4-MecdoaH2): X-ray crystal structures of [Cu(cdoa)(phen)2].8.8H(2)O and [Cu(4-Mecdoa)(phen)2].13H2O (phen=1,10-phenanthroline)

Two novel coumarin-based ligands, coumarin-6,7-dioxyacetic acid (1) (cdoaH(2)) and 4-methylcoumarin-6,7-dioxyacetic acid (2) (4-MecdoaH(2)), were reacted with copper(II) and manganese(II) salts to give [Cu(cdoa)(H(2)O)(2)].1.5H(2)O (3), [Cu(4-Mecdoa)(H(2)O)(2)] (4), [Mn(cdoa)(H(2)O)(2)] (5) and [Mn(4-Mecdoa)(H(2)O)(2)].0.5H(2)O (6). The metal complexes, 3-6, were characterised by elemental analysis, IR and UV-Vis spectroscopy, and magnetic susceptibility measurements and were assigned a polymeric structure. 1 and 2 react with Cu(II) in the presence of excess 1,10-phenanthroline (phen) giving [Cu(cdoa)(phen)(2)].8.8H(2)O (7) and [Cu(4-Mecdoa)(phen)(2)].13H(2)O (8), respectively. The X-ray crystal structures of 7 and 8 confirmed trigonal bipyramidal geometries, with the metals bonded to the four nitrogen atoms of the two chelating phen molecules and to a single carboxylate oxygen of the dicarboxylate ligand. The complexes were screened for their antimicrobial activity against a number of microbial species, including methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Candida albicans. The metal-free ligands 1 and 2 were active against all of the microbes. Complexes 3-6 demonstrated no significant activity whilst the phen adducts 7 and 8 were active against MRSA (MIC(80)=12.1microM), E. coli (MIC(80)=14.9microM) and Patonea agglumerans (MIC(80)=12.6microM). Complex 7 also demonstrated anti-Candida activity (MIC(80)=22microM) comparable to that of the commercially available antifungal agent ketoconazole (MIC(80)=25microM).