New cyanido-bridged iron(II) spin crossover coordination polymers with an unusual ladder-like topology: an alternative to Hofmann clathrates.

Two new cyanido-bridged {FeIIMII} double chains were obtained by reacting cyanido anions [M(CN)4]2- with complex cations [FeII(tptz)]2+ (preformed in situ by mixing a hydrated tetrafluoroborate salt of iron(II) and a tptz ligand, tptz = 2,4,6-tri(2-pyridyl)-1,3,5-triazine) having the general formula [FeII(tptz)MII(CN)4]·2H2O·CH3CN, where M = Pd (1) or Pt (2). Additionally, two molecular complexes formulated as [FeII(tptz)2][MII(CN)4]·4.25H2O, where M = Pd (3) or Pt (4), were subsequently obtained from the same reaction, as secondary products. Single crystal X-ray analysis revealed that 1 and 2 are isostructural and crystallize in the P-1 triclinic space group. Their structure consists of a double-chain with a ladder-like topology, in which cyanido-based [M(CN)4]2- metalloligands coordinate, through three CN- ligands and three [FeII(tptz)]2+ complex cations. Compounds 3 and 4 are also isostructural and crystallize in the P1̄ triclinic space group, and the X-ray structural data show the formation of [FeII(tptz)2]2+ and [MII(CN)4]2- ionic units interconnected through H-bonds and π⋯π stacking supramolecular interactions. The static DC magnetic measurements recorded in the temperature range of 2-300 K showed that 1 and 2 exhibit incomplete spin transition on cooling, which is also confirmed by single crystal XRD analysis and Mössbauer spectroscopy. Compounds 3 and 4 are diamagnetic, most likely due to the encapsulation of Fe(II) in a tight pocket formed by two tptz ligands that preserve the low-spin state in the temperature range of 2-400 K.

Antitumor Properties of a New Macrocyclic Tetranuclear Oxidovanadium(V) Complex with 3-Methoxysalicylidenvaline Ligand.

A wide variety of metal-based compounds have been obtained and studied for their antitumor activity since the intensely used cytostatic drugs (e.g., cisplatin) failed to accomplish their expected pharmacological properties. Thus, we aimed to develop a new vanadium-based drug and assess its antitumor properties using the human hepatocarcinoma (HepG2) cell line. The compound was synthesized from vanadyl sulfate, DL-valine, and o-vanillin and was spectrally and structurally characterized (UV-Vis, IR, CD, and single-crystal/powder-XRD). Compound stability in biological media, cell uptake, and the interaction with albumin were assessed. The mechanisms of its antitumor activity were determined compared to cisplatin by performing cytotoxicity, oxidative and mitochondrial status, DNA fragmentation, ß-Tubulin synthesis investigation, and cell cycle studies. Herein, we developed a macrocyclic tetranuclear oxidovanadium(V) compound, [(VVO)(L)(CH3O)]4, having coordinated four Schiff base (H2L) ligands, 3-methoxysalicylidenvaline. We showed that [(VVO)(L)(CH3O)]4: (i) has pH-dependent stability in biological media, (ii) binds to albumin in a dose-dependent manner, (iii) is taken up by cells in a time-dependent way, (iv) has a higher capacity to induce cell death compared to cisplatin (IC50 = 6 µM vs. 10 µM), by altering the oxidative and mitochondrial status in HepG2 cells. Unlike cisplatin, which blocks the cell cycle in the S-phase, the new vanadium-based compound arrests it in S and G2/M-phase, whereas no differences in the induction of DNA fragmentation and reduction of ß-Tubulin synthesis between the two were determined. Thus, the [(VVO)(L)(CH3O)]4 antitumor mechanism involved corroboration between the generation of oxidative species, mitochondrial dysfunction, degradation of DNA, cell cycle arrest in the S and G2/M-phase, and ß-Tubulin synthesis reduction. Our studies demonstrate the potent antitumor activity of [(VVO)(L)(CH3O)]4 and propose it as an attractive candidate for anticancer therapy.

Synthesis, Characterization, and In Vitro Insulin-Mimetic Activity Evaluation of Valine Schiff Base Coordination Compounds of Oxidovanadium(V).

Type 2 diabetes became an alarming global health issue since the existing drugs do not prevent its progression. Herein, we aimed to synthesize and characterize a family of oxidovanadium(V) complexes with Schiff base ligands derived from L-/D-valine (val) and salicylaldehyde (sal) or o-vanillin (van) as insulin-mimetic agents and to assess their potential anti-diabetic properties. Two new oxidovanadium(V) complexes, [{VVO(R-salval)(H2O)}(µ2-O){VVO(R-salval)}] and [{VVO(R-vanval)(CH3OH)}2(µ2-O)], and their S-enantiomers were synthesized and characterized. The compounds exhibit optical activity as shown by crystallographic and spectroscopic data. The stability, the capacity to bind bovine serum albumin (BSA), the cytotoxicity against human hepatoma cell line, as well as the potential anti-diabetic activity of the four compounds are investigated. The synthesized compounds are stable for up to three hours in physiological conditions and exhibit a high capacity of binding to BSA. Furthermore, the synthesized compounds display cytocompatibility at biologically relevant concentrations, exert anti-diabetic potential and insulin-mimetic activities by inhibiting the α-amylase and protein tyrosine phosphatase activity, and a long-term increase of insulin receptor phosphorylation compared to the insulin hormone. Thus, the in vitro anti-diabetic potential and insulin-mimetic properties of the newly synthesized oxidovanadium(V) compounds, correlated with their cytocompatibility, make them promising candidates for further investigation as anti-diabetic drugs.

Multibrominated hyperbranched polymers: synthesis and further functionalizations by ARGET ATRP or click chemistry.

Hyperbranched polymers with multiple alkyl bromide peripheral groups were synthesized by the copolymerization of styrene with ethylene glycol dimethacrylate (2.5, 5.0, 7.5, or 10.0 mol% relative to styrene) in the presence of CBr(4) (10-20-fold excess vs. the radical initiator). The latter compound markedly delayed the gelation and served as the source of terminal bromine atoms via transfer to the propagating radicals. The degree of branching increased with the amount of crosslinker. The alkyl bromide groups were used in further chemical modifications (ATRP at low catalyst concentration or azidation with NaN(3) followed by CuBr-catalyzed click coupling of an alkyne-terminated polymer) that yielded star copolymers with hyperbranched cores.

Thermodynamic, electrochemical, high-pressure kinetic, and mechanistic studies of the formation of oxo Fe(IV)-TAML species in water.

Stopped-flow kinetic studies of the oxidation of Fe(III)-TAML catalysts, [ F e{1,2-X(2)C(6)H(2)-4,5-( NCOCMe(2) NCO)(2)CMe(2)}(OH(2))](-) (1), by t-BuOOH and H(2)O(2) in water affording Fe(IV) species has helped to clarify the mechanism of the interaction of 1 with primary oxidants. The data collected for substituted Fe(III)-TAMLs at pH 6.0-13.8 and 17-45 °C has confirmed that the reaction is first order both in 1 and in peroxides. Bell-shaped pH profiles of the effective second-order rate constants k(I) have maximum values in the pH range of 10.5-12.5 depending on the nature of 1 and the selected peroxide. The "acidic" part is governed by the deprotonation of the diaqua form of 1 and therefore electron-withdrawing groups move the lower pH limit of the reactivity toward neutral pH, although the rate constants k(I) do not change much. The dissection of k(I) into individual intrinsic rate constants k(1) ([FeL(OH(2))(2)](-) + ROOH), k(2) ([FeL(OH(2))OH)](2-) + ROOH), k(3) ([FeL(OH(2))(2)](-) + ROO(-)), and k(4) ([FeL(OH(2))OH)](2-) + ROO(-)) provides a model for understanding the bell-shaped pH-profiles. Analysis of the pressure and substituent effects on the reaction kinetics suggest that the k(2) pathway is (i) more probable than the kinetically indistinguishable k(3) pathway, and (ii) presumably mechanistically similar to the induced cleavage of the peroxide O-O bond postulated for cytochrome P450 enzymes. The redox titration of 1 by Ir(IV) and electrochemical data suggest that under basic conditions the reduction potential for the half-reaction [Fe(IV)L(=O)(OH(2))](2-) + e(-) + H(2)O → [Fe(III)L(OH)(OH(2))](2-) + OH(-) is close to 0.87 V (vs NHE).

Catalase-peroxidase activity of iron(III)-TAML activators of hydrogen peroxide.

Exceptionally high peroxidase-like and catalase-like activities of iron(III)-TAML activators of H 2O 2 ( 1: Tetra-Amidato-Macrocyclic-Ligand Fe (III) complexes [ F e{1,2-X 2C 6H 2-4,5-( NCOCMe 2 NCO) 2CR 2}(OH 2)] (-)) are reported from pH 6-12.4 and 25-45 degrees C. Oxidation of the cyclometalated 2-phenylpyridine organometallic complex, [Ru (II)( o-C 6H 4py)(phen) 2]PF 6 ( 2) or "ruthenium dye", occurs via the equation [ Ru II ] + 1/2 H 2 O 2 + H +-->(Fe III - TAML) [ Ru III ] + H 2 O, following a simple rate law rate = k obs (per)[ 1][H 2O 2], that is, the rate is independent of the concentration of 2 at all pHs and temperatures studied. The kinetics of the catalase-like activity (H 2 O 2 -->(Fe III - TAML) H 2 O + 1/2 O 2) obeys a similar rate law: rate = k obs (cat)[ 1][H 2O 2]). The rate constants, k obs (per) and k obs (cat), are strongly and similarly pH dependent, with a maximum around pH 10. Both bell-shaped pH profiles are quantitatively accounted for in terms of a common mechanism based on the known speciation of 1 and H 2O 2 in this pH range. Complexes 1 exist as axial diaqua species [FeL(H 2O) 2] (-) ( 1 aqua) which are deprotonated to afford [FeL(OH)(H 2O)] (2-) ( 1 OH) at pH 9-10. The pathways 1 aqua + H 2O 2 ( k 1), 1 OH + H 2O 2 ( k 2), and 1 OH + HO 2 (-) ( k 4) afford one or more oxidized Fe-TAML species that further rapidly oxidize the dye (peroxidase-like activity) or a second H 2O 2 molecule (catalase-like activity). This mechanism is supported by the observations that (i) the catalase-like activity of 1 is controllably retarded by addition of reducing agents into solution and (ii) second order kinetics in H 2O 2 has been observed when the rate of O 2 evolution was monitored in the presence of added reducing agents. The performances of the 1 complexes in catalyzing H 2O 2 oxidations are shown to compare favorably with the peroxidases further establishing Fe (III)-TAML activators as miniaturized enzyme replicas with the potential to greatly expand the technological utility of hydrogen peroxide.

Mechanistically inspired design of Fe(III)-TAML peroxide-activating catalysts.

Recent broad-ranging mechanistic studies of FeIII-TAML peroxide activators enable a strategy for designing catalysts with improved (i) hydrolytic and (ii) operational stabilities, (iii) faster activation of H2O2 and other peroxides, and (iv) a pH of highest activity closer to 7. Combining all items of insight leads to [Fe{1-NO2C6H3-3,4-(NCOCMe2NCO)2CF2}(OH2)]- (1a) which exhibits the most desirable technical performance in its class.

Attaining control by design over the hydrolytic stability of Fe-TAML oxidation catalysts.

The iron(III) complexes of tetra amidato macrocyclic ligands (TAMLs) ([Fe{1-X1-2-X2C6H2-4,5-(NCOCMe2NCO)2CR2}(OH2)]- , 1: X1 = X2 = H, R2 = Me2 (a), R2 = (CH2)2 (b); X1 = X2 = Cl, R2 = F2 (c), etc.), which the proton is known to demetalate at pH < 3, are also subject to catalyzed demetalation by Brønsted acid buffer components at pH 4-9 such as H2PO4-, HSO3-, and CH3CO2H, HO2CCH2CO2-. Buffers based on pyridine (py) and tris(hydroxymethyl)aminomethane (TRIS) are catalytically inactive. Where reactions proceed, the products are demetalated TAMLs and iron species of variable composition. Pseudo-first-order rate constants for the demetalation (kobs) are linear functions of the acid concentrations, and the effective second-order rate constants k1,eff have a hyperbolic dependence on [H+] (k1,eff = a1[H+]/(b1+[H+]). The rate of demetalation of 1a in H2PO4-/HPO42- buffer is appreciable, but the kobs values for 1b and 1c are immeasurably low, showing that the rates are strongly affected by the CR2 or "tail" fragments, which are known to potently affect the TAML basicity. The reactivities of 1 depend insignificantly on the aromatic ring or "head" group of 1. The proposed mechanism involves precoordination of the acidic buffer species followed by hydrolysis. The demetalating abilities of buffer species depend on their structures and acidities. Thus, although pyridine-2-carboxylic (picolinic) acid catalyzes the demetalation, its 3- and 4-isomers (nicotinic and isonicotininc acids) are inactive. The difference is rationalized to result from the ability that only coordinated picolinic acid has to deliver a proton to an amidato nitrogen in an intramolecular manner. The reaction order in picolinic acid equals one for 1a and two for 1b. For 1b, "inactive" pyridine and nicotinic acid speed up the demetalation in the presence of picolinic acid, suggesting that the second order arises from the axial binding of two pyridine molecules, one of which must be picolinic acid. The binding of pyridine- and imidazole-type ligands was confirmed by UV/vis equilibrium measurements and X-ray crystallography. The implications of these mechanistic findings for designing superior Fe-TAML oxidation catalysts and catalyst formulations are discussed using the results of DFT calculations.

High-valent iron complexes with tetraamido macrocyclic ligands: structures, Mössbauer spectroscopy, and DFT calculations.

Iron complexes of tetraamido macrocyclic ligands (TAML) are unique synthetic oxidation catalysts. In general, the central Fe(III) ion (S=3/2) is surrounded by four, almost planar, deprotonated amide-N sigma-donors although the full suite with new generation systems includes some substitution of amides with related donor functionalities. Oxidation under different conditions affords a variety of high-valent forms of iron-TAMLs. This review provides a summary and discussion of structural and spectroscopic features of complexes oxidized by one equivalent above the ferric state. These comprise Fe(IV)-TAML high spin (S=2) and intermediate spin (S=1) systems, wherein the oxidation equivalent can be taken from the metal (Fe(IV)) or the ligand (TAML radical-cation Fe(III)), and coupled spin (S=0) systems of mu-oxoiron(IV) dimers. The discussion is principally based on data obtained by X-ray crystallography, Mössbauer spectroscopy, and density functional theory calculations.

Metal incorporation in modified PNA duplexes.

Substitution of bipyridine for a nucleobase leads to modified peptide nucleic acid (PNA) single strands that are bridged in the presence of Ni2+ into a duplex containing a combination of hydrogen and coordinative bonds. CD experiments demonstrate that the duplex adopts a structure similar to that of an unmodified 10-bp PNA duplex, and UV melting experiments show a very sensitive dependence of the duplex stability on the substitution of a nucleobase pair with a pair of ligands or a metal-ligand alternative base pair.