Synthesis and aqueous solution properties of multinuclear oxo-bridged vanadium(IV/V) complexes

Reaction of the multifunctional phenolic ligands 2,5-bis[N,N-bis(carboxymethyl)aminomethyl]hydroquinone (H6cahq), 2,2'-bis[N,N-bis(carboxymethyl)aminomethyl]-4,4'-isopropylidenediphen ol(H6capd),2,2',2'-tris[N,N-bis(carboxymethyl)aminomethyl]-1,1 ,1-tris(4-hydroxyphenyl)ethane (H9catp) and the monofunctional 2-[N,N-bis(carboxymethyl)aminomethyl]-4-carboxyphenol (H3cacp), with VOSO4 and NaVO3 affords the oxo-bridged mixed-valence vanadium(IV/V) Na6[(VO)4(mu-O)2(mu-cahq)2] x Na2SO4 x 20H2O (1), HnNa(3-n)[(VO)2(mu-O)(mu-cacp)2] (2), HnNa(3-n)[(VO)4(mu-O)2(mu-capd)2] (3), HnNa(9-n)[(VO)6(mu-O)3(mu3-catp)2] (4). In addition to the synthesis, we report the infrared, magnetic, optical and electrochemical properties of these complexes. The hydrolytic stability at different pH values was also investigated using visible spectroscopy.     

Structure–activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells

As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-O)(4)] to donate Ti(IV) to human apo-transferrin and its hydrolytic stability have been investigated and compared to the previously reported data on modified titanocenes with either hydrophilic ancillary ligands or the functionalized cyclopentadienyl ligands. Notably, the titanium-maltolato complex does not transfer Ti(VI) to human apo-transferrin at any time within the first seven days of its interaction, demonstrating the inert character of this species. Stability studies on these complexes have shown that titanocene complexes decompose at physiological pH while the [Ti(4)(maltolato)(8)(mu-O)(4)] complex is stable at this pH without any notable decomposition for a period of ten days. The antitumor activity of these complexes against colon cancer HT-29 cells was determined using an MTT cell viability assay at 72 and 96 h. The titanocene-amino acid and the (Cp-R)(2)TiCl(2)/(Cp-R)CpTiCl(2) (R = CO(2)CH(3)) complexes were not biologically active when human transferrin was absent; they also were inactive when human transferrin was present at dose-equivalent concentrations. (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(2)CH(3)) showed cytotoxic activity in HT-29 cells comparable to that which is displayed by titanocene dichloride. The titanium-maltolato complex had higher levels of cytotoxic activity than any other titanocene complex investigated. Transferrin may be important in protecting the titanium center from hydrolysis, but this may be achieved by selecting ligands that could result in hydrolytically stable, yet active, complexes.     

Ferric ion (hydr)oxo clusters in the “Venus flytrap” cleft of FbpA: M?ssbauer, calorimetric and mass spectrometric studies

Isothermal calorimetric studies of the binding of iron(III) citrate to ferric ion binding protein from Neisseria gonorrhoeae suggested the complexation of a tetranuclear iron(III) cluster as a single step binding event (apparent binding constant K(app) (ITC) = 6.0(5) × 10(5) M(-1)). High-resolution Fourier transform ion cyclotron resonance mass spectrometric data supported the binding of a tetranuclear oxo(hydroxo) iron(III) cluster of formula [Fe(4)O(2)(OH)(4)(H(2)O)(cit)](+) in the interdomain binding cleft of FbpA. The mutant H9Y-nFbpA showed a twofold increase in the apparent binding constant [K(app) (ITC) = 1.1(7) × 10(6) M(-1)] for the tetranuclear iron(III) cluster compared to the wild-type protein. M?ssbauer spectra of Escherichia coli cells overexpressing FbpA and cultured in the presence of added (57)Fe citrate were indicative of the presence of dinuclear and polynuclear clusters. FbpA therefore appears to have a strong affinity for iron clusters in iron-rich environments, a property which might endow the protein with new biological functions.     

Synthesis and oxidation of carboxylate-bridged diiron(II) complexes with substrates tethered to primary alkyl amine ligands

The synthesis and crystallographic characterization of a series of diiron(II) complexes with sterically hindered terphenyl carboxylate ligands and alkyl amine donors are presented. The compounds [Fe(2)(mu-O(2)CAr(Tol))(4)(L)(2)] (L=NH(2)(CH(2))(2)SBn (1); NH(2)(CH(2))(3)SMe (2); NH(2)(CH(2))(3)CCH (3)), where (-)O(2)CAr(Tol) is 2,6-di(p-tolyl)benzoate, and [Fe(2)(mu-O(2)CAr(Xyl))(2)(O(2)CAr(Xyl))(2)(L)(2)] (L=NH(2)(CH(2))(3)SMe (4); NH(2)(CH(2))(3)CCH (5)), where (-)O(2)CAr(Xyl) is 2,6-di(3,5-dimethylphenyl)benzoate, were prepared as small molecule mimics of the catalytic sites of carboxylate-bridged non-heme diiron enzymes. The compounds with the (-)O(2)CAr(Tol) carboxylate form tetrabridged structures, but those containing the more sterically demanding (-)O(2)CAr(Xyl) ligand have only two bridging ligands. The ancillary nitrogen ligands in these carboxylate-rich complexes incorporate potential substrates for the reactive metal centers. Their oxygenation chemistry was studied by product analysis of the organic fragments following decomposition. Compound 1 reacts with dioxygen to afford PhCHO in approximately 30% yield, attributed to oxidative dealkylation of the pendant benzyl group. Compound 3 decomposes to form Fe(II)Fe(III) and Fe(III)Fe(IV) mixed-valence species by established bimolecular pathways upon exposure to dioxygen at low temperatures. Upon decomposition, the alkyne-substituted amine ligand was recovered quantitatively. When the (-)O(2)CAr(Tol) carboxylate was replaced by the (-)O(2)CAr(Xyl) ligand in 5, different behavior was observed. The six-coordinate iron(III) complex with one bidentate and two monodentate carboxylate ligands, [Fe(O(2)CAr(Xyl))(3)(NH(2)(CH(2))(3)CCH)(2)] (6), was isolated from the reaction mixture following oxidation.     

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.     

Characterization of synthetic oxomanganese complexes and the inorganic core of the O2-evolving complex in photosystem II: evaluation of the DFT/B3LYP level of theory

The capabilities and limitations of the Becke-3-Lee-Yang-Parr (B3LYP) hybrid density functional are investigated as applied to studies of mixed-valent multinuclear oxomanganese complexes. Benchmark calculations involve the analysis of structural, electronic and magnetic properties of di-, tri- and tetra-nuclear Mn complexes, previously characterized both chemically and spectroscopically, including the di-mu-oxo bridged dimers [Mn(III)Mn(IV)(mu-O)(2)(H(2)O)(2)(terpy)(2)](3+) (terpy=2,2':6,2'-terpyridine) and [Mn(III)Mn(IV)(mu-O)(2)(phen)(4)](3+) (phen=1,10-phenanthroline), the Mn trimer [Mn(3)O(4)(bpy)(4)(H(2)O)(2)](4+) (bpy=2,2'-bipyridine), and the tetramer [Mn(4)O(4)L(6)](+) with L=Ph(2)PO(2)(-). Furthermore, the density functional theory (DFT) B3LYP level is applied to analyze the hydrated Mn(3)O(4)CaMn cluster completely ligated by water, OH(-), Cl(-), carboxylate and imidazole ligands, analogous to the '3+1 Mn tetramer' of the oxygen-evolving complex of photosystem II. It is found that DFT/B3LYP predicts structural and electronic properties of oxomanganese complexes in pre-selected spin-electronic states in very good agreement with X-ray and magnetic experimental data, even when applied in conjunction with rather modest basis sets. However, it is conjectured that the energetics of low-lying spin-states is beyond the capabilities of the DFT/B3LYP level, constituting a limitation to mechanistic studies of multinuclear oxomanganese complexes where until now the performance of DFT/B3LYP has raised little concern.     

Carbohydrate-appended 3-hydroxy-4-pyridinone complexes of the [M(CO)3]+ core (M = Re, 99mTc, 186Re)

This work describes the use of 3-hydroxy-4-pyridinone ligands for binding the [M(CO)(3)](+) core (M = Re, Tc) in the context of preparing novel Tc(I) and Re(I) glucose conjugates. Five pyridinone ligands bearing pendent carbohydrate moieties, HL(1-5), were coordinated to the [M(CO)(3)](+) core on the macroscopic scale (M = Re) and on the tracer scale (M = (99m)Tc, (186)Re). On the macroscopic scale the complexes, ReL(1-5)(CO)(3)(H(2)O), were thoroughly characterized by mass spectrometry, IR spectroscopy, UV-visible spectroscopy, elemental analysis, and 1D/2D NMR spectroscopy. Characterization confirmed the bidentate coordination of the pyridinone and the pendent nature of the carbohydrate and suggests the presence of a water molecule in the sixth coordination site. In preliminary biological evaluation, both the ligands and complexes were assessed as potential substrates or inhibitors of hexokinase, but showed no activity. Labeling via the [(99m)Tc(CO)(3)(H(2)O)(3)](+) precursor gave the tracer species (99m)TcL(1-5)(CO)(3)(H(2)O) in high radiochemical yields. Similar high radiochemical yields when labeling with (186)Re were facilitated by in situ preparation of the [(186)Re(CO)(3)(H(2)O)(3)](+) species in the presence of HL(1-5) to give (186)ReL(1-5)(CO)(3)(H(2)O). Stability challenges, incubating (99m)TcL(1-5)(CO)(3)(H(2)O) in the presence of excess cysteine and histidine, confirmed complex stability up to 24 h.     

Electron transfer kinetics and mechanistic study of the thionicotinamide coordinated to the pentacyanoferrate(III)/(II) complexes: a model system for the in vitro activation of thioamides anti-tuberculosis drugs

The mechanism of activation thioamide-pyridine anti-tuberculosis prodrugs is poorly described in the literature. It has recently been shown that ethionamide, an important component of second-line therapy for the treatment of multi-drug-resistant tuberculosis, is activated through an enzymatic electron transfer (ET) reaction. In an attempt to shed light on the activation of thioamide drugs, we have mimicked a redox process involving the thionicotinamide (thio) ligand, investigating its reactivity through coordination to the redox reversible [Fe(III/II)(CN)(5)(H(2)O)](2-/3-) metal center. The reaction of the Fe(III) complex with thionicotinamide leads to the ligand conversion to the 3-cyanopyridine species coordinated to a Fe(II) metal center. The rate constant, k(et)=10 s(-1), was determined for this intra-molecular ET reaction. A kinetic study for the cross-reaction of thionicotinamide and [Fe(CN)(6)](3-) was also carried out. The oxidation of thionicotinamide by [Fe(CN)(6)](3-) leads to formation of mainly 3-cyanopyridine and [Fe(CN)(6)](4-) with a k(et)=(5.38+/-0.03) M(-1)s(-1) at 25 degrees C, pH 12.0. The rate of this reaction is strongly dependent on pH due to an acid-base equilibrium related to the deprotonation of the R-SH functional group of the imidothiol form of thionicotinamide. The kinetic results reinforced the assignment of an intra-molecular mechanism for the ET reaction of [Fe(III)(CN)(5)(H(2)O)](2-) and the thioamide ligand. These results can be valuable for the design of new thiocarbonyl-containing drugs against resistant strains of Mycobacterium tuberculosis by a self-activating mechanism.     

The photorelease of nitrogen monoxide (NO) from pentacyanonitrosyl coordination compounds of group 8 metals.

The photodetachment of NO from [M(II)(CN)5NO]2- with M = Fe, Ru, and Os, upon laser excitation at various wavelengths (355, 420, and 480 nm) was followed by various techniques. The three complexes showed a wavelength-dependent quantum yield of NO production Phi(NO), as measured with an NO-sensitive electrode, the highest values corresponding to the larger photon energies. For the same excitation wavelength the decrease of Phi(NO) at 20 degrees C in the order Fe > Ru > Os, is explained by the increasing M-N bond strength and inertness of the heavier metals. Transient absorption data at 420 nm indicate the formation of the [M(III)(CN)5H2O]2- species in less than ca. 1 micros for M = Fe and Ru. The enthalpy content of [Fe(III)(CN)5H2O]2- with respect to the parent [Fe(II)(CN)5NO]2- state is (190 +/- 20) kJ mol(-1), as measured by laser-induced optoacoustic spectroscopy (LIOAS) upon excitation at 480 nm. The production of [Fe(III)(CN)5H2O]2- is concomitant with an expansion of (8 +/- 3) ml mol(-1) consistent with an expansion of the water bound through hydrogen bonds to the CN ligands plus the difference between NO release into the bulk and water entrance into the first coordination sphere. The activated process, as indicated by the relatively strong temperature dependence of the Phi(NO) values and by the temperature dependence of the appearance of the [Fe(III)(CN)5H2O]2- species, as determined by LIOAS, is attributed to NO detachment in less than ca. 100 ns from the isonitrosyl (ON) ligand (MS1 state).     

Synthesis, structure and interactions with DNA of novel tetranuclear, [Mn4(II/II/II/IV)] mixed valence complexes

Reaction of Mn(II) with phenoxyalkanoic acids and di-2-pyridyl ketone oxime (Hpko) leads to neutral tetranuclear complexes of the general formula Mn(4)(O)(pko)(4)(phenoxyalkanoato)(4) (phenoxyalkanoic acids: H-mcpa=2-methyl-4-chloro-phenoxy-acetic acid, H-2,4,5-T=2,4,5-trichloro-phenoxy-acetic acid or H3,4-D=3,4-dichloro-phenoxy-acetic acid). The compounds were synthesized by adding di-2-pyridyl ketone oxime to MnCl(2) in the presence of the sodium salts of the alkanoic acids in methanol. The crystal structure of Mn(4)(II/II/II/IV)(O)(pko)(4)(2,4,5-T)(4).2.5CH(3)OH.0.25H(2)O 1 shows that the complex consists of a [Mn(4)(mu(4)-O)](8+) core with a Mn(IV) and 3 Mn(II) ions in octahedral environment and a mu(4)-O atom bridging the four manganese ions. Spectroscopic studies of the interaction of these tetranuclear clusters with DNA showed that these compounds bind to dsDNA. The binding strength of the Mn(4)(II/II/II/IV)(O)(pko)(4)(2,4,5-T)(4) complex for calf thymus DNA is equal to 1.1x10(4)M(-1). Among the deoxyribonucleotides they bind preferentially to deoxyguanylic acid (dGMP). Competitive studies with ethidium bromide (EthBr) showed that the Mn(4)(II/II/II/IV)(O)(pko)(4)(2,4,5-T)(4) complex exhibited the ability to displace the DNA-bound EthBr indicating that the complex binds to DNA via intercalation in strong competition with EthBr for the intercalative binding site. Additionally, DNA electrophoretic mobility experiments showed that all three complexes, at low cluster concentration, are obviously capable of binding to pDNA causing its cleavage (relaxation) at physiological pH and temperature. At higher cluster concentration, catenated dimer forms of pDNA was formed.     

Inhibition of the purified 20S proteasome by non-heme iron complexes

Polypyridyl pentadentate ligands N4Py (1) and Bn-TPEN (2), along with their respective iron complexes, have been investigated for their ability to inhibit the purified 20S proteasome. Results demonstrated that the iron complexes of both ligands are potent inhibitors of the 20S proteasome (IC(50) = 9.2 μM for [Fe(II)(OH(2))(N4Py)](2+) (3) and 4.0 μM for [Fe(II)(OH(2))(Bn-TPEN)](2+) (4)). Control experiments showed that ligand 1 or Fe(II) alone showed no inhibition, whereas 2 was moderately active (IC(50) = 96 μM), suggesting that iron, when bound to these ligands, plays a key role in proteasome inhibition. Results from time-dependent inactivation studies suggest different modes of action for the iron complexes. Time-dependent decay of proteasome activity was observed upon incubation in the presence of 4, which accelerated in the presence of DTT, suggesting reductive activation of O(2) and oxidation of the 20S proteasome as a mode of action. In contrast, loss of 20S proteasome activity was not observed with 3 over time, suggesting inhibition through direct binding of the iron complex to the enzyme. Inhibition of the 20S proteasome by 4 was not blocked by reactive oxygen species scavengers, consistent with a unique oxidant being responsible for the time-dependent inhibition observed.     

Solution equilibrium studies on metal complexes of 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) and models: catecholate versus hydroxamate coordination in iron(III)-, aluminium(III)- and molybdenum(VI)-Dopaha complexes

Equilibrium results based on pH potentiometric, spectrophotometric and (1)H NMR measurements for the complexes of Fe(III), Al(III) and Mo(VI) with 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) as well as for binary model systems Fe(III)-, Al(III)-, Mo(VI)-acetohydroxamic acid (Aha), -alpha-alaninehydroxamic acid (alpha-Alaha) and -1,2-dihydroxy-3,5-benzene-disulphonate (Tiron) and ternary model systems Fe(III)-, Al(III)-, Mo(VI)-Tiron-Aha, are summarized in this paper. The amine-type coordination mode is not detectable with these metal ions at all. Precipitation occurs at pH <5.5 with Fe(III) and Al(III) even at a Dopaha-to-metal ion ratio of 10:1. Hydroxamate-type coordination was demonstrated with both metals below the pH range of precipitation but, after dissolution, catecholate-type coordination was exclusively found. The hydroxamate-type coordination mode occurs only in the very acidic pH range for Mo(VI) complexes and the crossover from hydroxamate to catecholate binding occurs at pH >3. A ligand-bridged dinuclear species, [(MoO(2))(2)(Dopaha)(2)](2+), involving mixed-type (catecholate and hydroxamate) coordination modes is formed in the pH range 2.5-5.5. [MoO(2)A(2)H(2)], with catecholate-type coordination, forms above pH 3. On increasing the pH further, deprotonation of the coordinated Dopaha and hydrolytic processes result in the formation of catecholate-coordinated [MoO(3)AH] and [MoO(3)A]. MoO(4)(2-) and free Dopaha exist above pH 10.     

Bridging-type changes facilitate successive oxidation steps at about 1 V in two binuclear manganese complexes--implications for photosynthetic water-oxidation

The redox behavior of two synthetic manganese complexes illustrates a mechanistic aspect of importance for light-driven water oxidation in Photosystem II (PSII) and design of biomimetic systems (artificial photosynthesis). The coupling between changes in oxidation state and structural changes was investigated for two binuclear manganese complexes (1 and 2), which differ in the set of first sphere ligands to Mn (N(3)O(3) in 1, N(2)O(4) in 2). Both complexes were studied by electron paramagnetic resonance (EPR) and X-ray absorption spectroscopy (XAS) in three oxidation states which had been previously prepared either electro- or photochemically. The following bridging-type changes are suggested. In 1: Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(II)<-->Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(III)-->Mn(III)-(mu-OR)(mu-OCO)(mu-O)-Mn(III). In 2: Mn(II)-(mu-OR)(mu-OCO)(2)-Mn(III)<-->Mn(III)-(mu-OR)(mu-OCO)(2)-Mn(III)-->Mn(III)-(mu-OR)(mu-OCO)(mu-O)-Mn(IV). In both complexes, the first one-electron oxidation proceeds without bridging-type change, but involves a redox-potential increase by 0.5-1V. The second one-electron oxidation likely is coupled to mu-oxo-bridge (or mu-OH) formation which seems to counteract a further potential increase. In both complexes, mu-O(H) bridge formation is associated with a redox transition proceeding at approximately 1V, but the mu-O(H) bridge is observed at the Mn(2)(III,III) level in 1 and at the Mn(III,IV) level in 2, demonstrating modulation of the redox behavior by the terminal ligands. It is proposed that also in PSII bridging-type changes facilitate successive oxidation steps at approximately the same potential.     

Reactions of peroxyl radicals with Fe(H(2)O)(6)(2+)

The reactions of RO(2)* radicals with Fe(H(2)O)(6)(2+) were studied, R[double bond]H; CH(3); CH(2)COOH; CH(2)CN; CH(2)C(CH(3))(2)OH; CH(2)OH; CHCl(2)/CCl(3). All these processes involve the following reactions: Fe(H(2)O)(6)(2+)+RO(2)*<==>(H(2)O)(5)Fe(III)[bond]OOR(2+) K(1) approximately 250 M(-1); (H(2)O)(5)Fe(III)[bond]OOR(2+)+H(3)O(+)/H(2)O-->Fe(H(2)O)(6)(3+)+ROOH+H(2)O/OH(-); (H(2)O)(5)Fe(III)[bond]OOR(2+)+2Fe(H(2)O)(6)(2+)-->3Fe(H(2)O)(6)(3+)+ROH; 2 RO(2)*-->Products; RO(2)*+(H(2)O)(5)Fe(III)[bond]OOR(2+)-->Fe(H(2)O)(6)(2+)+products. The values of k(1) and k(3) [reaction is clearly not an elementary reaction] approach the ligand exchange rate of Fe(H(2)O)(6)(2+), i.e. these reactions follow an inner sphere mechanism and the rate determining step is the ligand exchange step. The rate of reaction is several orders of magnitude faster than that of the Fenton reaction. Surprisingly enough the K(1) values are nearly independent of the redox potential of the radical and are considerably higher than calculated from the relevant redox potentials. These results indicate that the ROO(-) ligands considerably stabilise the Fe(III) complex, this stabilisation is smaller for radicals with electron withdrawing groups which raise the redox potential of the radical but decrease the basicity of the ROO(-) ligands, two effects which seem to nearly cancel each other. Finally, the results clearly indicate that reaction (5) is relatively fast and affects the nature of the final products. The contribution of these reactions to oxidation processes involving 'Fenton-like' processes is discussed.     

Synthesis, characterization and antitumor studies of Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) complexes of N-salicyloyl-N'-o-hydroxythiobenzhydrazide

A new ligand N-salicyloyl-N'-o-hydroxythiobenzhydrazide (H2Sotbh) forms complexes [Mn(HSotbh)2], [Fe(Sotbh-H)(H2O)2], [M(Sotbh)] [M=Co(II), Cu(II) and Zn(II)] and [Ni(Sotbh)(H(2)O)2], which were characterized by various physico-chemical techniques. M?ssbauer spectrum of [Fe(Sotbh-H)(H2O)2] reveals the quantum admixture of 5/2 and 3/2 spin-states. Mn(II), Cu(II) and Ni(II) complexes were observed to inhibit the growth of tumor in vitro, whereas, Fe(III), Co(II), Zn(II) complexes did not. In vivo administration of Mn(II), Cu(II) and Ni(II) resulted in prolongation of survival of tumor bearing mice. Tumor bearing mice administered with Mn(II), Cu(II) and Ni(II) complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implication of the H2Sotbh and its metal complexes in tumor regression and tumor growth associated immunosuppression.     

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.     

N,N-bis(2-mercaptoethyl)methylamine: a new coligand for Tc-99m labeling of hydrazinonicotinamide peptides

Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with Tc(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries. Tridentate ligands, such as bis(mercaptoethyl)methylamine (NS2), may constrain the possible coordination geometries and improve overall stability. To investigate this, we synthesized NS2, converted the [Tc-mannitol-For-MLFK-HYNIC] to the corresponding NS2-containing complex [Tc-NS2-For-MLFK-HYNIC], and compared its infection imaging and biodistribution properties with [Tc-mannitol-For-MLFK-HYNIC]. Conversion to the NS2 complex was confirmed by HPLC which showed a single unique hydrophobic species with retention time greater than the [Tc-mannitol-For-MLFK-HYNIC] complex. Imaging experiments with both preparations were performed in rabbits with E. coli infections in the left thigh. Tissue radioactivity measurements demonstrated that compared to Tc-mannitol-peptide, accumulation of Tc-NS2-peptide was lower in blood, heart, and normal muscle and higher in spleen, infected muscle, and pus (p < 0.01). These results indicate that the Tc-NS2-peptide complex is chemically more homogeneous and exhibits improved infection localization and biodistribution properties. In an effort to model the interactions of the metal-HYNIC core with NS2 and related ligand types, the reactions of [ReCl3(NNC5H4NH)(NHNC5H4N)] and [99TcCl3(NNC5H4NH)(NHNC5H4N)], effective structural analogues for the [M(NNC5H4NH(x))2] core, with NS2, C5H3N-2,6-(CH2SH)2, O(CH2CH2SH)2, and S(CH2CH2SH)2 were investigated and the compounds [M[CH3N(CH2CH2S)2](NNC5H4N)(NHNC5H4N] (M = 99Tc (5a), Re (5b)), [Re[C5H3N-2,6-(CH2S)2](NNC5H4N)(NHNC5H4N)].CH2Cl2.0.5MeOH (7), [Re[SCH2CH2)2O] (NNC5H4N)(NHNC5H4N)] (8), and [Re[(SCH2CH2)2S](NNC5H4NH)(NHNC5H4N)]Cl (9) were isolated. Similarly, the reaction of [ReCl3(NNC5H4NH)(NHNC5H4N)] with the bidentate ligands pyridine-2-methanethiol and 3-(trimethlysilyl)pyridine-2-thiol led to the isolation of [ReCl(C5H4N-2-CH2S) (NNC5H4N)(NHNC5H4N)] (10) and [Re(2-SC5H3N-3-SiMe3)2 (NNC5H4N)(NHNC5H4N)] (11), respectively, while reaction with N-methylimidazole-2-thiol yielded the binuclear complex [Re(OH)Cl(SC3H2N2CH3)2(NNC5H4N)2 (NHNC5H4N)2] (12). The analogous metal-(HYNIC-OH) precursor, [ReCl3[NNC5H3NH(CO2R)] [NHNC5H3N(CO2R)]] (R = H, 13a; R = CH3, 13b) has been prepared and coupled to lysine to provide [RCl3[NNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)] [NHNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)]].2HCl (14.2HCl), while the reaction of the methyl ester 13b with 2-mercaptopyridine yields [Re(2-SC5H4N)2[NNC5H3N(CO2Me)][NHNC5H3N(CO2Me)]] (15). While the chemical studies confirm the robustness of the M-HYNIC core (M = Tc, Re) and its persistence in ligand substitution reactions at adjacent coordination sites of the metal, the isolation of oligomeric structures and the insolubility of the peptide conjugates of 13, 14, and 15 underscore the difficulty of characterizing these materials on the macroscopic scale, an observation relevant to the persistent concerns with reagent purity and identity on the tracer level.     

A linear correlation between energy of LMCT band and oxygenation reaction rate of a series of catecholatoiron(III) complexes: initial oxygen binding during intradiol catechol oxygenation

The oxygen reactivity of catecholatoiron(III) complexes has been examined using a series of catecholate ligands as the substrate. All the complexes examined here, [Fe(III)(TPA)(R-Cat)]BPh(4) (1-9) (TPA: tris(pyridin-2-ylmethyl)amine; R-Cat: substituted catecholate ligand, R=3,5-(t)Bu(2) (1), 3,6-(t)Bu2 (2), 3,5-Me2 (3), 3,6-Me2 (4), 4-(t)Bu (5), 4-Me (6), H (7), 4-Cl (8) and 3-Cl (9)), exclusively afforded the intradiol cleaving products of the catecholate ligands upon exposure to O2. It was revealed that 1-7 can be categorized into two classes based on their electrochemical properties; i.e., the complexes having the dialkyl-substituted (group A) and the mono- or non-substituted (group B) catecholate ligands. In spite of their classification, these two groups show a linear correlation between the logarithm of the reaction rate constant with O2 and the energy of the catecholate-to-iron(III) LMCT band, although 2 shows a large negative deviation from the correlation line. Based on this LMCT-energy dependent reactivity of 1 and 3-9 as well as the very low reactivity of 2, we have discussed on the mechanisms of the reaction of [Fe(III)(TPA)(R-Cat)]BPh4 with O2.     

Characterisation of Ca- and Al-pectate gels by thermal analysis and FT-IR spectroscopy

Thermal analysis (TG-DTA) and FT-IR spectroscopy have been performed on calcium-pectate membranes to investigate their structure and the consequent variation caused by aluminium sorption. Calcium-polygalacturonate (Ca-PG) membranes, model systems of the soil-root interface, were exposed to aluminium solutions at different concentrations (25-800 microM). Three different pHs (3.50, 4.00 and 4.50) were chosen to study the influence of different aluminium species, such as [Al(H2O)6]3+, [Al(OH)(H2O)5]2+ and [Al(OH)2(H2O)(4)]+, on the structure of the Ca-PG membrane. The DTA profiles and FT-IR spectra showed how aluminium sorption induces structural modifications leading to a reorganisation of the chain aggregates and a weakening of the structure. Higher pH, that is, 4.00 and 4.50, and thus hydrolytic aluminium species and related higher calcium content maintain a more regular structure than at pH 3.50. At pH 3.50, both the effect of [Al(H2O)6]3+ and a major calcium release had a greater impact and thus induced a greater weakening of the structure.     

Polynuclear diorganotin(IV) complexes with arylhydroxamates: Syntheses, structures and in vitro cytotoxic activities

Series of polynuclear diorganotin(IV) complexes with di-halogenbenzohydroxamate ligands (substituents=2,4-Cl(2), 2,4-F(2), 3,4-F(2), 2,5-F(2), 2,6-F(2)), formulated as the polymeric [R(2)SnL](n)a (1:1) and the tetranuclear [R(4)Sn(2)(HL)(2)(L)](2)b (2:3) (HL=arylhydroxamate), were prepared and characterized by FT-IR, (1)H, (13)C, (119)Sn NMR spectroscopies, elemental analyses and melting point measurements. X-ray diffraction analyses were also carried out for the representative complexes [Me(2)Sn{2,4- F(2)C(6)H(3)C(O)NO}](n)2a and [n-Bu(4)Sn(2){2,4- F(2)C(6)H(3)C(O)NHO}(2) {2,4-F(2)C(6)H(3)C(O)NO}] (2)1b and show that the ligated mono- and di-basic forms, HL and L, of the arylhydroxamic acid (H(2)L) display the oxamic and oximic tautomeric forms, respectively. These compounds exhibit in vitro cytotoxicities toward human leukemic promyelocites HL-60, BGC-823, BEL-7402 and KB cell lines which, in some cases, are identical to, or even higher than, that of "cisplatin". The polymeric diorganotin/hydroxamato complexes a containing the long carbon chain butyl ligands are the most active ones, and the dependence of the antitumor activity of the complexes on various factors, namely the nuclearity, the organic ligand, the type, position and number of the X ring substituents, is also discussed.