Electrochemical measurements confirm the preferential bonding of the antimetastatic complex [ImH][RuCl(4)(DMSO)(Im)] (NAMI-A) with proteins and the weak interaction with nucleobases

An electrochemical and biological study of interaction between the prototypical antimetastatic drug imidazolium trans-tetrachlorodimethylsulfoxideimidazoleruthenate (III) complex, [ImH][RuCl(4)(DMSO)(Im)] (DMSO = dimethylsulfoxide, Im = imidazole), nicknamed NAMI-A, and several biomolecules, namely DNA, bovine (BSA) and human (HSA) serum albumin, is reported. Electrochemistry offers great advantages over the existing devices based on optical techniques, since it provides rapid, simple, and low-cost information whether the interaction occurs or not. Moreover, we describe some biochemical assays to test the interaction of NAMI-A with ribonucleoprotein telomerase and protein Taq polymerase. All the data confirm the preferential interaction of NAMI-A with proteins with respect to nucleotides, especially when compared with the behaviour of the well-known alkylating drug cisplatin in the presence of the same targets.     

Synthesis, crystal structures, and anti-convulsant activities of ternary [Zn(II)(3,5-diisopropylsalicylate)(2)], [Zn(II)(salicylate)(2)] and [Zn(II)(aspirinate)(2)] complexes

Following observations that bis(3,5-diisopropylsalicylato)diaquazinc(II), [Zn(II)(3,5-DIPS)(2)(H(2)O)(2)], had anti-convulsant activity, bis(acetylsalicylate)diaquazinc(II), [Zn(II)(aspirinate)(2)(H(2)O)(2)], and the Zn(II) ternary 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neocuproine, NC) or dimethyl sulfoxide (DMSO) complexes of Zn(II)3,5-diisopropylsalicylate, salicylate, and acetylsalicylate were synthesized and spectroscopically characterized. Anti-convulsant and Rotorod toxicity activities of these complexes were determined to examine their anti-convulsant and undesirable central nervous stimulant or depressant activities of these Zn(II) non-steroidal anti-inflammatory agent complexes. Bis(3,5-diisopropylsalicylato)-1,10-phenanthorlinezinc(II), [Zn(II)(3,5-DIPS)(2)(phen)], (1) has one bidentate phen ligand and two mono-deprotonated 3,5-DIPS ligands. One of the carboxylates bonds in an asymmetric chelating mode. The Zn(II) atom exhibits a distorted bicapped rectangular pyramidal environment N(2)O(2)OO (4+1+1 *). In the neocuproine complex, bis(3,5-diisopropylsalicylato)-2,9-dimethyl-1,10-phenanthorlinezinc(II), [Zn(II)(3,5-DIPS)(2)(NC)] (2), the Zn(II) atom has a much more distorted bicapped rectangular pyramidal environment, N(2)O(2)O(2) (4+2 *), compared to 1. The two carboxylate ligands exhibit the same asymmetric coordinating mode with longer metalloelement-oxygen bond distances compared to 1. The space group of [Zn(II)(aspirinate)(2)(H(2)O)(2)] (3), which has been reported as Cc is corrected to C2/c. The zinc atom exhibits a (4+2 *) bicapped square pyramidal environment. While the two ternary phenanthroline-containing complexes, 1 and 2, evidenced weak protection against maximal electroshock (MES)- and subcutaneous Metrazol (scMET) induced seizures, [Zn(II)(3,5-DIPS)(2)(DMSO)(2)], [Zn(II)(aspirinate)(2)(H(2)O)(2)], and bis(salicylato)-1,10-phenanthorlinezinc(II), [Zn(II)(salicylate)(2)(phen)], were found to be particularly useful in protecting against MES and scMET seizures and [Zn(II)(aspirinate)(2)(H(2)O)(2)] and [Zn(II)(salicylate)(2)(phen)] were found to have activity in protecting against Psychomotor seizures, without causing Rotorod toxicity. Activities of these and other Zn(II) complexes of non-steroidal anti-inflammatory agents are consistent with the well-known anti-inflammatory responses of Zn(II)-dependent enzymes. There was also some evidence of Rotorod toxicity consistent with a mechanism of action involving sedative-hypnotic activity of recognized anti-epilepticdrugs.     

Hydrolysis and cytotoxic properties of osmium(II)/(III)-DMSO-azole complexes. Short communication

The antiproliferative properties of the osmium(II) complexes cis,fac-[Os(II)Cl(2)(DMSO)(3)(L)] and trans,cis,cis-[Os(II)Cl(2)(DMSO)(2)(L)(2)] (L = 1H-pyrazole, 1H-imidazole) were studied in three human cancer cell lines, namely 41M (ovary), SK-BR-3 (breast), and SW480 (colon). Their activities were compared with those of osmium(III) and ruthenium(III) NAMI-A type complexes on HT-29 (colon) and SK-BR-3 cancer cell lines. While IC(50) values of all the Os(II) complexes were found to be >1000 microM in all cell lines, Os and Ru-NAMI-A type complexes showed remarkable antiproliferative activity. The marginal in vitro cytotoxicity of the Os(II) compounds is presumably attributed to their resistance to hydrolysis. However, the Os-NAMI-A complexes, which are also kinetically stable in aqueous solution, showed reasonable antiproliferative activity in vitro when compared with the analogous Ru compounds and with the Os(II)-DMSO-azole species, indicating that hydrolysis might be not a prerequisite for the antitumor activity of Os-NAMI-A type complexes.     

Molecular structure, bioavailability and bioactivity of [Cu(o-phen)2(cnge)](NO3)2.2H2O and [Cu(o-phen)(cnge)(H2O)(NO3)2] complexes

Two Cu(II) complexes with cyanoguanidine (cnge) and o-phenanthroline, [Cu(o-phen)(2)(cnge)](NO(3))(2).2H(2)O (1) and [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)] (2), have been synthesized using different experimental techniques and characterized by elemental analyses, FTIR, diffuse and UV-vis spectra and EPR and magnetic moment measurements techniques. The crystal structures of both complexes were solved by X-ray diffraction methods. Complex (1) crystallizes in the monoclinic space group C2/c with a=12.621(5), b=31.968(3), c=15.39(1)A, beta=111.68(4) degrees, and Z=8 and complex (2) in the monoclinic space group P2(1)/n with a=10.245(1), b=13.923(2), c=12.391(2)A, beta=98.07(1) degrees, and Z=4. The environments of the copper(II) center are trigonal bipyramidal (TBP) for [Cu(o-phen)(2)(cnge)](2+) and an elongated octahedron for [Cu(o-phen)(cnge)(H(2)O)(NO(3))(2)]. Solution studies have been performed to determine the species distribution. The superoxide dismutase (SOD) activities of both complexes have also been tested in order to determine if these compounds mimic the enzymatic action of the enzyme SOD that protects cells against peroxide radicals.     

On the lability of dimethylsulfoxide (DMSO) coordinated to the [Ru(II)-NO(+)] species: X-ray structures of mer-[RuCl(3)(DMSO)(2)(NO)] and mer-[RuCl(3)(CD(3)CN)(DMSO)(NO)

The syntheses of nitrosyl–dimethylsulfoxide–ruthenium(II) complexes with general formula mer-[RuCl₃(L)(DMSO)(NO)] (L=DMSO or CD₃CN) is reported. The mer-[RuCl₃(DMSO)₂(NO)] (1) complex was obtained from the reaction of [RuCl₃(NO)] with the sulfoxide ligand in acetone. The mer-[RuCl₃(CD₃CN)(DMSO)(NO)] (2) compound was obtained from mer-[RuCl₃(DMSO)₂(NO)] maintained in deuterated acetonitrile. These data suggest a slow kinetic reaction due the low lability of the DMSO ligand coordinated to the {Ru^II–NO⁺} species. The crystal and molecular structures of (1) and (2) have been determined from X-ray studies. Crystal data: for (1), monoclinic, P2₁/c, a=8.8340(2) Å, b=12.0230(3) Å, c=13.7064(4) Å, β=114.546(2)°, Z=4, R1=0.0429; for (2), monoclinic, P21/n, a=10.0180(7) Å, b=9.5070(7) Å, c=13.3340(9) Å, β=102.264(4)°, Z=4, R1=0.0472. The spectroscopic characterization of (1), in solid state (infrared spectrum) and in solution (nuclear magnetic resonance and cyclic voltammetry) is also described.     

Mechanistic information on the reaction of cis- and trans-[RuCl2(DMSO)4] with d(T2GGT2) derived from MALDI-TOF and HPLC studies

Reactions of trans and cis isomers of the Ru(II) complex [RuCl(2)(DMSO)(4)] with single-stranded hexanucleotide d(T(2)GGT(2)) were studied in aqueous solutions in the absence and presence of excess chloride by high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF MS). Despite the different reactive species formed from the two isomers in aqueous solution, similar reaction products are obtained in their interaction with d(T(2)GGT(2)). Both [RuCl(2)(DMSO)(4)] isomers bind to the oligonucleotide in the bidentate mode to form thermodynamically stable bis-guanosine adducts, Ru(G-N7)(2). Significant differences were observed in the reaction rates, however the reaction with trans- [RuCl(2)(DMSO)(4)] is ca. 5-10 times faster in comparison to that observed for the cis analogue. This difference is interpreted in terms of different rate-limiting steps for the trans and cis complexes, respectively. It is suggested that the rate of the reaction with the trans isomer is controlled by dissociation of a Cl(-) ligand from the initially formed trans,cis,cis-[RuCl(2)(DMSO)(2)(H(2)O)(2)]. In the contrast, release of a dimethyl sulfoxide molecule from the reactive species cis,fac-[RuCl(2)(DMSO)(3)(H(2)O)] is likely to be rate limiting for the cis analogue. Significant influence of electrostatic interactions on the reaction rate was observed for the trans isomer. Mechanistic interpretation of the observed reactivity trends based on data obtained from UV-Vis spectroscopy, HPLC and MALDI-TOF MS studies is presented and discussed within the paper.     

Low-temperature (180 K) crystal structure,electron paramagnetic resonance spectroscopy,and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates

The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.     

Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2] (L=o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to [Ru(azpy)2Cl2]

The dichlorobis(2-phenylazopyridine)ruthenium(II) complexes, [Ru(azpy)(2)Cl(2)], are under renewed investigation due to their potential anticancer activity. The three most common isomers alpha-, beta- and gamma-[RuL(2)Cl(2)] with L= o-tolylazopyridine (tazpy) and 4-methyl-2-phenylazopyridine (mazpy) (alpha indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, trans, cis positions, beta indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, cis, cis positions, and gamma indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual trans, cis, cis positions) are synthesized and characterized by NMR spectroscopy. The molecular structures of gamma-[Ru(tazpy)(2)Cl(2)] and alpha-[Ru(mazpy)(2)Cl(2)] are determined by X-ray diffraction analysis. The IC(50) values of the geometrically isomeric [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] complexes compared with those of the parent [Ru(azpy)(2)Cl(2)] complexes are determined in a series of human tumour cell lines (MCF-7, EVSA-T, WIDR, IGROV, M19, A498 and H266). These data unambiguously show for all complexes the following trend: the alpha isomer shows a very high cytotoxicity, whereas the beta isomer is a factor 10 less cytotoxic. The gamma isomers of [Ru(tazpy)(2)Cl(2)] and [Ru(mazpy)(2)Cl(2)] display a very high cytotoxicity comparable to that of the gamma isomer of the parent compound [Ru(azpy)(2)Cl(2)] and to that of the alpha isomer. These biological data are of the utmost importance for a better understanding of the structure-activity relationships for the isomeric [RuL(2)Cl(2)] complexes.     

Syntheses and DNA-binding studies of two ruthenium(II) complexes containing one ancillary ligand of bpy or phen: [Ru(bpy)(pp[2,3]p)2](ClO4)2 and [Ru(phen)(pp[2,3]p)2](ClO4)2

Two new ruthenium(II) complexes of [Ru(bpy)(pp[2,3]p)2](ClO4)2 and [Ru(phen)(pp[2,3]p)2](ClO4)(2) (bpy=2,2'-bipyridine, phen=1,10-phenanthroline, pp[2,3]p=pyrido[2',3':5,6]pyrazino[2,3-f][1,10]phenanthroline) have been synthesized and characterized by elemental analysis and 1H NMR spectra. The calf thymus DNA-binding properties of the two complexes were investigated by UV-visible and emission spectroscopy, competitive binding experiments with ethidium bromide and viscosity measurements. The results indicate that the two complexes intercalate between the base pairs of the DNA tightly with intrinsic DNA-binding constants of 3.08 x 10(6) and 6.53 x 10(6) M(-1) in buffered 50 mM NaCl, respectively, which are much larger than 6.9 x 10(5) M(-1) for [Ru(bpy)2(pp[2,3]p)](ClO4)2 containing two ancillary ligands of bpy.     

New dimanganese(III) complexes of pentadentate (N2O3) Schiff base ligands with the [Mn2(mu-OAc)(mu-OR)2]3+ core: synthesis, characterization and mechanistic studies of H2O2 disproportionation

Two new diMn(III) complexes [Mn(2)(III)L(1)(mu-AcO)(mu-MeO)(methanol)(2)]Br (1) and [Mn(2)(III)L(2)(mu-AcO)(mu-MeO)(methanol)(ClO(4))] (2) (L(1)H(3)=1,5-bis(2-hydroxybenzophenylideneamino)pentan-3-ol; L(2)H(3)=1,5-bis(2-hydroxynaphtylideneamino)pentan-3-ol) were synthesized and structurally characterized. Structural studies evidence that these complexes have a bis(mu-alkoxo)(mu-carboxylato) triply bridged diMn(III) core in the solid state and in solution, with two substitution-labile sites--one on each Mn ion--in cis-position. The two complexes show catalytic activity toward disproportionation of H(2)O(2), with saturation kinetics on [H(2)O(2)], in methanol and dimethyl formamide at 25 degrees C. Spectroscopic monitoring of the H(2)O(2) disproportionation reaction suggests that (i) complexes 1 and 2 dismutate H(2)O(2) by a mechanism involving redox cycling between Mn(2)(III) and Mn(2)(IV), (ii) the complexes retain the dinuclearity during catalysis, (iii) the active form of the catalyst contains bound acetate, and (iv) protons favors the formation of inactive Mn(II) species. Comparison to other dimanganese complexes of the same family shows that the rate of catalase reaction is not critically dependent on the redox potential of the catalyst, that substitution of phenolate by naphtolate in the Schiff base ligand favors formation of the catalyst-substrate adduct, and that, in the non-protic solvent, the bulkier substituent at the imine proton position hampers the binding to the substrate.     

The crystal structures of copper(II), manganese(II), and nickel(II) complexes of a (Z)-2-hydroxy-N'-(2-oxoindolin-3-ylidene) benzohydrazide--potential antitumor agents

Mononuclear complexes of Cu(II), Ni(II), and Mn(II) with a new Schiff base ligand derived from indoline-2,3-dione and 2-hydroxybenzohydrazide, [Cu(II)(L)(2)], [Ni(II)(L)(2)], and [Mn(II)L.(AcO).2C(2)H(5)OH] [HL=(Z)-2-hydroxy-N'-(2-oxoindolin-3-ylidene)benzohydrazide], have been prepared. The complexes have been structurally characterized by X-ray crystallography. Among the three complexes, the Cu(II) complex had the novel highest antitumor activity.     

Complexes trans-[RuCl(2)(nic)(4)] and trans-[RuCl(2)(i-nic)(4)] as free radical scavengers

This study evaluates the action of the new ruthenium complexes trans-RuCl(2)(nic)(4)] (I) and trans-[RuCl(2)(i-nic)(4)] (II) as free radical scavengers. In our experiments, both compounds acted as scavengers of superoxide anion (O(2)*(-)), hydroxyl radicals (HO*) and nitrogen monoxide (formally known as 'nitric oxide'; NO*). In addition, complexes I and II potentiated the release of NO* from S-nitroso-N-acetyl-DL-penicilamine (SNAP), a NO* donor. Complex II, but not I, also decreased the nitrite levels in culture media of activated macrophages. A hypsochromic shift of lambda(max) and a significant change in half-wave potential (E(1/2)) was observed when NO* was added to the Complex II. Thiobarbituric reactive substance (TBARS) levels were significantly reduced in rats treated for 1 week with Complex II plus tert-butylhydroperoxide, when compared to rats treated only with tert-butylhydroperoxide. None of the complexes showed cytotoxicity. These findings support the suggestion that the new ruthenium complexes, especially trans-[RuCl(2)(i-nic)(4)] or its derivatives, might provide potential therapeutic benefits in disorders where reactive nitrogen (RNS) or oxygen (ROS) species are involved.     

Reaction of the octahedral antitumor complex trans-RuCl2 (DMSO)4 with 2'deoxyguanosine.

The reaction of the antitumor octahedral complex trans-RuCl2(DMSO)4 with 2'deoxyguanosine leads to the reversible formation of two diastereoisomeric monoadducts and one biadduct. This shows that it is possible to accommodate two purine bases in a cis configuration in an octahedral transition metal complex which exhibits antiblastic activity. All the product compounds are characterized by a guanine moiety coordination via the N7 atom. A marked decrease (about two pK units) is observed for the N1H pKa of the coordinated guanine moieties. The reversibility of the monodentate binding could explain the low toxicity of the ruthenium(II) complexes.     

Evaluating hydrogen bond interactions in enzymes containing Mn(III)-histidine complexation using manganese-imidazole complexes

It is often difficult to control hydrogen bond interactions in small molecule compounds that model metalloenzyme active sites. The imidazole-containing ligands 4,5-dicarboxyimidazole (H(3)DCBI) and 4,5-dicarboxy- N-methylimidazole (H(2)MeDCBI) allow examination of the effects of internal hydrogen bonding between carboxylate and imidazole nitrogen atoms. A new series of mononuclear manganese imidazole complexes have been prepared using these ligands: Mn(III)(salpn)(H(2)DCBI)(DMF) (1), Mn(III)(salpn)(HMeDCBI) (2), Mn(III)(dtsalpn)(HMeDCBI) (3), [Mn(IV)(dtsalpn)(HMeDCBI)]PF(6) (4), Mn(III)(salpn)(H(2)DCBI) (5), Mn(III)(dtsalpn)(H(2)DCBI) (6), and Mn(IV)(dtsalpn)(H(2)DCBI)PF(6) (8). Complexes 1, 2, 3, 5, and 6 have been prepared by direct reaction of salpn [salpn=(salicylideneaminato)-1,3-diaminopropane)] or dtsalpn [dtsalpn=(3,5-di- t-butylsalicylideneaminato)-1,3-diaminopropane)] and H(3)DCBI and H(2)MeDCBI with Mn(III) acetate, while complexes 4 and 8 were made by bulk electrolysis of complex 3 or 6 in dichloromethane. Complexes 1, 2, and 6 were characterized by X-ray diffraction. The impact of hydrogen bonding interactions of the complexes has been demonstrated by X-ray diffraction, cyclic voltammetry, and EPR spectroscopy. In all complexes the central metal ion is present in a six-coordinate geometry. Magnetic susceptibility measurements confirm the spin and oxidation states of the complexes. The cyclic voltammograms of 3 and 6 in dichloromethane reveal single, reversible redox waves with E(1/2)=600 mV and 690 mV, respectively. The X-band EPR spectrum of 4 shows a broad signal around g=4.4, and the corresponding complex 8 possesses a broad signal at slightly lower field ( g=5.5) than 4. These studies demonstrate that even small changes in the effective charge of the imidazole ligand can have a profound impact on the structure, spectroscopy, and magnetism of manganese(IV) complexes. We use these observations to present a model that may explain the origin of the g=4.1 signal in the S(2) state of photosystem II.     

Solution, solid state and biological characterization of ruthenium(III)-DMSO complexes with purine base derivatives

Two new complexes of Ru(III) with purine base derivatives, [mer-RuCl(3)(acv)(DMSO-S)(C(2)H(5)OH)].C(2)H(5)OH (1) (acv=acyclovir, DMSO=dimethyl sulfoxide) and [trans-RuCl(4)(guaH)(DMSO-S)].2H(2)O (2) (guaH=protonated molecule of guanine), were prepared from the same Ru(III) precursor, [trans-RuCl(4)(DMSO-S)(2)](-), by substitution of one DMSO-S. Coordination of acv induced also replacement of one chloride by an ethanol molecule. This reactivity difference was explained by striking contrasts in the hydrogen bonding schemes of the two complexes, evidenced in their X-ray crystal structures. In 1 the guanine derivative acyclovir is coordinated to ruthenium through the N(7) atom, while in 2 the protonated guanine molecule is bound through the N(9) atom. Both complexes were also characterized by various physico-chemical methods in the solid state and in the solution. In vitro, the biological activity of 2 and of the previously described complexes [mer-RuCl(3)(acv)(DMSO-S)(CH(3)OH)].0.5CH(3)OH (3) and [mer-RuCl(3)(acv)(DMSO-S)(H(2)O)].H(2)O (4) on tumour cells appear to be very similar to that of NAMI-A (NAMI-A=[ImH][trans-RuCl(4)(DMSO-S)Im]). All compounds are only weakly active on tumour cell proliferation but show an interesting proadhesive effect that suggest possible activity on tumour malignancy.     

Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity

The synthesis and characterization of complexes [(η(6)-arene)Ru(N,N')X][PF(6)], where arene is para-cymene (p-cym), biphenyl (bip), ethyl benzoate (etb), hexamethylbenzene (hmb), indane (ind) or 1,2,3,4-tetrahydronaphthalene (thn), N,N' is 2,2'-bipyrimidine (bpm) and X is Cl, Br or I, are reported, including the X-ray crystal structures of [(η(6)-p-cym)Ru(bpm)I][PF(6)], [(η(6)-bip)Ru(bpm)Cl][PF(6)], [(η(6)-bip)Ru(bpm)I][PF(6)] and [(η(6)-etb)Ru(bpm)Cl][PF(6)]. Complexes in which N,N' is 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione or 4,7-diphenyl-1,10-phenanthroline (bathophen) were studied for comparison. The Ru(II) arene complexes undergo ligand-exchange reactions in aqueous solution at 310?K; their half-lives for hydrolysis range from 14 to 715?min. Density functional theory calculations on [(η(6)-p-cym)Ru(bpm)Cl][PF(6)], [(η(6)-p-cym)Ru(bpm)Br][PF(6)], [(η(6)-p-cym)Ru(bpm)I][PF(6)], [(η(6)-bip)Ru(bpm)Cl][PF(6)], [(η(6)-bip)Ru(bpm)Br][PF(6)] and [(η(6)-bip)Ru(bpm)I][PF(6)] suggest that aquation occurs via an associative pathway and that the reaction is thermodynamically favourable when the leaving ligand is I?>?Br?≈?Cl. pK (a)* values for the aqua adducts of the complexes range from 6.9 to 7.32. A binding preference for 9-ethylguanine (9-EtG) compared with 9-ethyladenine (9-EtA) was observed for [(η(6)-p-cym)Ru(bpm)Cl][PF(6)], [(η(6)-hmb)Ru(bpm)Cl](+), [(η(6)-ind)Ru(bpm)Cl](+), [(η(6)-thn)Ru(bpm)Cl](+), [(η(6)-p-cym)Ru(phen)Cl](+) and [(η(6)-p-cym)Ru(bathophen)Cl](+) in aqueous solution at 310?K. The X-ray crystal structure of the guanine complex [(η(6)-p-cym)Ru(bpm)(9-EtG-N7)][PF(6)](2) shows multiple hydrogen bonding. Density functional theory calculations show that the 9-EtG adducts of all complexes are thermodynamically preferred compared with those of 9-EtA. However, the bmp complexes are inactive towards A2780 human ovarian cancer cells. Calf thymus DNA interactions for [(η(6)-p-cym)Ru(bpm)Cl][PF(6)] and [(η(6)-p-cym)Ru(phen)Cl][PF(6)] consist of weak coordinative, intercalative and monofunctional coordination. Binding to biomolecules such as glutathione may play a role in deactivating the bpm complexes.     

Ternary copper(II) complexes with N-carboxymethyl-l-prolinato(2-) ion and imidazole or creatinine: a comparative study of the interligand interactions influencing the molecular recognition and stability

The compounds {[Cu(CMP)(Him)].H(2)O}(n) (I) and [Cu(CMP)(crea)H(2)O].3H(2)O (II) were synthesized and characterized by X-ray diffraction, thermal, spectral and magnetic methods (CMP=N-carboxymethyl-;l-prolinato(2-) ion, Him=imidazole and crea=creatinine). Appropriate structural comparison with other compounds such as {[Cu(CMP)(H(2)O)].H(2)O}(n), [Cu(crea)(2)Cl(2)] and [Cu(dipeptide)(crea)(H(2)O)(x)].nH(2)O (x=0 or 1) have been made in order to prove that crea can act as an imidazole-like ligand (because it is able to promote the same fac- to mer-CMP tridentate conformational change in copper(II) complexes) as well as to discuss the interligand interactions which control the 'Cu(CMP) complex-crea, molecular recognition processes. In contrast to that found in related ternary complexes, we have concluded that direct CMP-crea interligand interactions are missing in the Cu-CMP-crea complex due to the inappropriate correspondence between the donor and/or acceptor H-bonding properties of these ligands. CMP can only act as H-acceptor by its two terminal carboxylate group, and crea can display H-donor and H-acceptor roles by its exocyclic -NH(2) and O moieties, respectively. That promotes the reinforcement of the Cu-N(crea) bond by a bridge -N-H(crea)...O(aqua) (2.867(3)A, 176.4 degrees).     

Low-temperature (180 K) crystal structures of tetrakis-mu-(niflumato)di(aqua)dicopper(II) N,N-dimethylformamide and N,N-dimethylacetamide solvates, their EPR properties, and anticonvulsant activities of these and other ternary binuclear copper(II)niflumate complexes

Two pseudopolymorphs, solvates, of [Cu(2)(II)(niflumate)(4)(H(2)O)(2)] of unknown structure were obtained following solution of [Cu(2)(II)(niflumate)(4)(H(2)O)(2)] in N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF). Low-temperature crystal structures obtained for these solvates revealed that they were ternary aqua DMA and DMF solvates: [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMA and [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMF. Intermolecular hydrogen bonding interactions account for the formation of these stable DMA and DMF solvates. These pseudopolymorphs contain a centrosymmetric binuclear center with Cu-Cu bond distances ranging from 2.6439(7) to 2.6452(9) A; the coordination sphere of Cu(II) is characterized by one long Cu-O (water) bond length of 2.128(3)-2.135(3) A and four short Cu-O (carboxylate) bonds of 1.949(3)-1.977(3) A. Crystal parameters for the DMA pseudopolymorph: a=10.372(1), b=19.625(2), c=17.967(2) A, beta=97.40(1) degrees , V=3626.8(6) A(3); monoclinic system; space group: P2(1)/a and for the DMF pseudopolymorph: a=10.125(2), b=18.647(3), c=19.616(4) A, alpha=74.38(2)(o), beta=88.18(2)(o), gamma=79.28(2)(o), V=3504(1) A(3); triclinic system; space group: P1. EPR spectra of these solids are identical and show strong antiferromagnetic coupling between the copper atoms, similar to the spectrum obtained for [Cu(2)(II)(niflumate)(4)(DMSO)(2)]. The [Cu(2)(II)(niflumate)(4)(H(2)O)(2)], [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMA, [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMF, [Cu(2)(II)(niflumate)(4)(DMF)(2)], and[Cu(2)(II)(niflumate)(4)(DMSO)(2)] evidenced protection against maximal electroshock-induced seizures and Psychomotor seizures at various times after treatment, consistent with the well known antiinflammatory activities of Cu chelates, but failed to protect against Metrazol-induced seizures while evidencing some Rotorod Toxicity consistent with a mechanism of action involving sedative activity.     

Synthesis,characterization and antitumor studies of transition metal complexes of o-hydroxydithiobenzoate

o-Hydroxydithiobenzoate (o-HOdtb) forms complexes, [Ni(o-HOdtb)(o-HOdtbS)], [Cu(o-Odtb)], [Co(o-HOdtb)(3)], [Fe(2)(o-Odtb)(3)], [Bu(n)(4)N][V(o-Odtb)(3)] and [Bu(n)(4)N][Zn(o-HOdtb)(3)] which were characterized by analyses and physicochemical studies. The bonding sites of o-HOdtb and the geometry of the complexes were determined by magnetic susceptibility, IR, ESR, NMR, M?ssbauer and electronic spectral data. The structure of [Bu(n)(4)N][Zn(o-HOdtb)(3)] and H(2)C(o-HOdtb)(2) were assigned by single crystal X-ray diffraction studies. The monomeric complex [Bu(n)(4)N][Zn(o-HOdtb)(3)] crystallizes in Pna2(1) space group. The M?ssbauer spectra of [Fe(2)(o-Odtb)(3)] at 298 and 80K suggest the presence of high spin iron(III) with an S=5/2 state. All the metal complexes were observed to inhibit the growth of tumor in vitro, whereas, ligand did not. In vivo administration of these complexes resulted in prolongation of survival of tumor-bearing mice. Tumor bearing mice administered with metal complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implication of the ligand and its metal complexes in tumor regression and tumor growth associated immunosuppression.     

Cytotoxic activity of platinum (II) complexes with tri-n-butylphosphine. Crystal structure of the dinuclear hydrazine-bridged complex, cis,cis-[PtCl(PBu3n)2(mu-N2H4)PtCl(PBu3n) 2] (ClO4)2.2CHCl3.

A series of platinum(II) tri-n-butylphosphine complexes having the formulas cis-[PtCl2L2], NEt4[PtCl3L], [PtCl(en)L]Cl, [Pt(en)L2](ClO4)2, sym-trans-[Pt2Cl4L2], [Pt2Cl2L4](ClO4)2, trans,trans-[PtCl2L(mu-N2H4)PtCl2L] trans,trans-[PtCl2L(mu-en)PtCl2L], and cis,cis-[PtClL2(mu-N2H4)PtClL2](ClO4)2 (L = tri-n-butylphosphine; en = ethylenediamine) have been synthesized and their cytotoxic activity in vitro and in vivo has been studied. The solution behavior of the novel dinuclear diamine-bridged platinum(II) complexes has been investigated by means of UV and 31P NMR spectroscopy. For the ionic hydrazine compound cis,cis-[PtClL2(mu-N2H4)PtClL2](ClO4)2, an x-ray structure determination is reported. Crystal data: space group P2(1)/a, a = 17.803(1), b = 18.888(3), c = 12.506(3) A, beta = 107.97(2) degrees, Z = 2, R = 0.052, RW = 0.058. The platinum coordination is approximately square-planar, with the bond lengths Pt-Cl = 2.358(5), Pt-N = 2.15(1), Pt-P(trans to Cl) = 2.260(5), and Pt-P(trans to N) = 2.262(6) A. All investigated compounds were cytotoxic in vitro against L1210 cells and showed no cross-resistance to cisplatin. On the other hand, no antitumor activity was observed vs L1210 leucemia in DBA2 mice.