Characterization and evaluation of pyrone and tropolone chelators for use in metalloprotein inhibitors

The tetrahedral zinc and cobalt complexes [(Tp^Ph,Me)ZnOH] (Tp^Ph,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) and [(Tp^Ph,Me)CoCl] were combined with 3-hydroxy-2H-pyran-2-one (3,2-pyrone), 3-hydroxy-4H-pyran-4-one (3,4-pyrone), and tropolone to form the corresponding [(Tp^Ph,Me)M(L)] complexes (L = bidentate ligand, M = Zn²⁺, Co²⁺). X-ray crystal structures of these complexes were obtained to determine the mode of binding for each chelator and the coordination geometry of each complex. The complexes [(Tp^Ph,Me)M(3,2-pyrone)] (M = Zn²⁺, Co²⁺) are the first structurally characterized metal complexes with this chelator. These complexes with the various chelators show that the cobalt(II) complexes are generally isostructural with their zinc(II) counterparts. In addition to structural characterization, inhibition data for each ligand against two different zinc(II) metalloproteins, matrix metalloproteinase-3 (MMP-3) and anthrax lethal factor (LF), were obtained. Examination of these chelators in the MMP-3 active site demonstrates the possible mode of inhibition.     

Template synthesis of macrocyclic complexes and their spectroscopic and antibacterial studies

A new series of macrocyclic complexes of type [M(TML)X]X₂, where M = Cr(III), Fe(III), TML is tetradentate macrocyclic ligand, and X = Cl^?, NO₃^?, CH₃COO^?, have been synthesized by condensation of isatin and ethylenediamine in the presence of metal salt. The complexes were synthesized by both conventional and microwave methods. The complexes have been characterized with the help of elemental analysis, conductance measurement, magnetic measurement, and infrared, far infrared, and electronic spectral studies. Molar conductance values indicate them to be 1:2 electrolytes. Electronic spectra along with magnetic moments suggest five-coordinate square pyramidal geometry for these complexes. The complexes were also tested for their in vitro antibacterial activity. Some of the complexes showed satisfactory antibacterial activitiy.     

Mn 2+ , and Zn 2+ 1:1 complexes with biochemically significant thioether carboxylic acids and some of the sulfoxide and sulfone derivatives

The 1:1 complexes of Mn²⁺, Cu²⁺, and Zn²⁺ with S-carboxymethyl alkyl and S-carboxymethyl aryl mercaptans were studied in water containing 50% dioxane (I = 0.1; t = 25 °). The determination of the stability constants and a comparison with simple carboxylate complexes reveals that the complexes of Cu²⁺ (and slightly also of Zn²⁺) with the S-carboxymethyl alkyl mercaptans are more stable than expected from only basicity of the carboxylate groups. This suggests that the thioether group participates in complex formation, i.e., chelates are formed. The Mn²⁺ complexes of both kinds of ligands, and the Cu²⁺ or Zn²⁺ complexes with S-carboxymethyl aryl mercaptans have the stability expected according to the basicity of the carboxylate groups. NMR experiments with S-carboxymethyl ethyl mercaptan confirm the formation of chelates with Cu²⁺ and suggest simple carboxylate complexes with Mn²⁺. Analogous experiments with (S-carboxymethyl phenyl mercaptan do not allow an unequivocal statement about the distribution between simple carboxylate complexes and chelates for both metal ions. Also, as the thioether acids are biologically oxidized, the complex stabilities of several of such oxidized derivatives were measured.     

Synthesis of green emissive terbium(III) complexes for displays: Optical,electrochemical and photoluminescent analysis

A series of heteroleptic terbium(III) complexes with fluorinated 2-thenoyltrifluoroacetone (TTFA) and other heteroaromatic units have been synthesized. The developed heteroleptic complexes were inspected via elemental study, cyclic voltammetry, thermal analysis and spectroscopic investigations. Optical band-gap data proposed the conducting property of prepared complexes. The photoluminescence emission profiles illustrated peaks based on terbium(III) cation (Tb³⁺) positioned at ~617, 586, 546 and 491 nm, imputed to ⁵D₄ to ⁷F_J (J = 3,4,5,6) transitions separately. Most intense peak at 546 nm corresponding to ⁵D₄ → ⁷F₅ transition is accountable for the green emissive character of developed complexes. The luminous character of complexes reveals the sensitization of Tb³⁺ by ligands. Color parameters further corroborates the green emanation of Tb³⁺ complexes. The photometric characteristics of complexes recommended their usages in designing display devices.     

Complex formation by 3 H-aldosterone in rat kidney and liver

Low molecular weight polar complexes were shown to be formed $\text{in vivo}$ from ³H-aldosterone in both kidney and liver subcellular fractions, the majority being present in the cytosol fractions. Significant differences were observed between the quantities of polar complexes present in kidney subcellular fractions from intact and adrenalectomized male rats and also between the quantities of these kidney polar complexes from spironolactone treated male rats. ³H-aldosterone macro-molecule complexes were shown to exist in appreciable quantities only in the kidney cytosol fractions of adrenalectomized male rats. These gel filtration studies also showed the ³H-aldosterone labeled macromolecule complexes to consist of two protein peaks; one of high molecular weight and the other of lower molecular weight (～50,000 mol. wt.). The amount of ³H-aldosterone labeled protein complexes in kidney cytosol was greatly reduced when adrenalectomized rats were pretreated $\text{in vivo}$ with spironolactone.     

Stability and structure of binary and ternary complexes of alpha-lipoate and lipoate derivatives with Mn2+, Cu2+, and Zn2+ in solution.

The stabilities of the 1:1 complexes of Mn²⁺, Cu²⁺, and Zn²⁺ with lipoate and its chainshortened catabolites, viz., bisnorlipoate and tetranorlipoate, were studied by potentiometric titrations in water containing 50% dioxane (I = 0.1, NaClO₄; 25 °C). A comparison of the stabilities of these complexes with those of simple carboxylates reveals that the catabolite complexes formed with Cu²⁺ and Zn²⁺ are more stable than expected from only the basicity of the carboxylate groups. This is evidence that chelates involving the disulfide group are formed. The stability of all Mn²⁺ complexes is determined by the basicity of the carboxylate groups. The same pattern of stability holds for the mixed-ligand complexes formed by Cu²⁺ or Zn²⁺, 2,2′-bipyridyl, and lipoate or one of its derivatives. It is evident that the disulfide group of the 1,2-dithiolane moiety can participate in the formation of binary and ternary complexes. The somewhat less-pronounced coordinating properties of the 1,2-dithiolane moiety compared with the tetrahydrothiophene moiety are discussed. It is apparent that the electron density at S(1) and S(2) in the dithiolane moiety of lipoate is not equivalent: S(1) is favored over S(2) in electrophilic reactions; possible biological implications are indicated.     

Fluorescent studies on the interaction of DNA and ternary lanthanide complexes with cinnamic acid‐phenanthroline and antibacterial activities testing

Twelve lanthanide complexes with cinnamate (cin^–) and 1,10‐phenanthroline (phen) were synthesized and characterized. Their compositions were assumed to be RE(cin)₃phen (RE³⁺ = La³⁺, Pr³⁺, Nd³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺, Dy³⁺, Ho³⁺, Tm³⁺, Yb³⁺, Lu³⁺). The interaction mode between the complexes and DNA was investigated by fluorescence quenching experiment. The results indicated the complexes could bind to DNA and the main binding mode is intercalative binding. The fluorescence quenching constants of the complexes increased from La(cin)₃phen to Lu(cin)₃phen. Additionally, the antibacterial activity testing showed that the complexes exhibited excellent antibacterial ability against Escherichia coli, and the changes of antibacterial ability are in agreement with that of the fluorescence quenching constants. Copyright © 2014 John Wiley & Sons, Ltd.     

Redox properties of iron–dithiocarbamates and their nitrosyl derivatives: implications for their use as traps of nitric oxide in biological systems

While the Fe²⁺–dithiocarbamate complexes have been commonly used as NO traps to estimate NO production in biological systems, these complexes can undergo complex redox chemistry. Characterization of this redox chemistry is of critical importance for the use of this method as a quantitative assay of NO generation. We observe that the commonly used Fe²⁺ complexes of N-methyl-D-glucamine dithiocarbamate (MGD) or diethyldithiocarbamate (DETC) are rapidly oxidized under aerobic conditions to form Fe³⁺ complexes. Following exposure to NO, diamagnetic NO–Fe³⁺ complexes are formed as demonstrated by the optical, electron paramagnetic resonance and gamma-resonance spectroscopy, chemiluminescence and electrochemical methods. Under anaerobic conditions the aqueous NO–Fe³⁺–MGD and lipid soluble NO–Fe²⁺–DETC complexes gradually self transform by reductive nitrosylation into paramagnetic NO–Fe²⁺–MGD complexes with yield of up to 50% and the balance is converted to Fe³⁺–MGD and nitrite. In dimethylsulfoxide this process is greatly accelerated. More efficient transformation of NO–Fe³⁺–MGD into NO–Fe²⁺–MGD (60–90% levels) was observed after addition of reducing equivalents such as ascorbate, hydroquinone or cysteine or with addition of excess Fe²⁺–MGD. With isotope labeling of the NO–Fe³⁺–MGD with ⁵⁷Fe, it was shown that these complexes donate NO to Fe²⁺–MGD. NO–Fe³⁺–MGD complexes were also formed by reversible oxidation of NO–Fe²⁺–MGD in air. The stability of NO–Fe³⁺–MGD and NO–Fe²⁺–MGD complexes increased with increasing the ratio of MGD to Fe. Thus, the iron–dithiocarbamate complexes and their NO derivatives exhibit complex redox chemistry that should be considered in their application for detection of NO in biological systems.     

Synthesis and characterization of Ru(II), Rh(III) and Ir(III) complexes of the “Daniphos” ligands and their application in the hydrogen transfer catalysis

The synthesis of arene-ruthenium(II) and C₅Me₅-rhodium(III) and -iridium(III) complexes of chiral arene-chromium-tricarbonyl-based P^∧P and P^∧N ligands is described. Three complexes were characterized in the solid state by X-ray structural analysis. The complexes were tested in the catalytic hydrogen transfer reactions as well as in the kinetic resolution of racemic alcohols, where some complexes showed good conversion, but low enantioselectivity.     

Synthesis,spectroscopic, and antibacterial activity of tetraazamacrocyclic complexes of trivalent chromium,manganese, and iron

A new series of macrocyclic complexes of type [M(TML)X]X₂, where M = Cr(III), Mn(III), or Fe(III), TML is tetradentate macrocyclic ligand, and X = Cl^?, NO₃^?, CH₃COO^? for Cr(III), Fe(III) and X = CH₃COO^? for Mn (III), has been synthesized by condensation of benzil and succinyldihydrazide in the presence of metal salt. The complexes have been so formulated due to the 1:2 electrolytic nature of these complexes as shown by conductivity measurements. The complexes have been characterized with the help of various physicochemical techniques such as elemental analysis, molar conductance, electronic and infrared spectral studies, and magnetic susceptibility. On the basis of these studies, a five-coordinate distorted square pyramidal geometry, in which two nitrogens and two carbonyl oxygen atoms are suitably placed for coordination toward the metal ion, has been proposed for all the complexes. The complexes have been tested for their in vitro antibacterial activity. Some of the complexes show remarkable antibacterial activities against some selected bacterial strains. The minimum inhibitory concentrations shown by these complexes have been compared with those shown by some standard antibiotics such as linezolid and cefaclor.     

Chemical and biological evaluation of 153Sm and 166Ho complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylphosphonic acid monoethylester) (H4 dotp OEt)

The novel methylphosphonic acid monoethylester (H₄dotp^OEt) has been synthesized and characterized and their complexes with Sm(III) and Ho(III) ions were studied. Dissociation constants of the ligand are lower than those of H₄dota. The stability constants of the Ln(III)-H₄dotp^OEt complexes are surprisingly much lower that those of H₄dota (H₄dota = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) probably due to a lower coordination ability of the phosphonate monoester groups. Acid-assisted decomplexation studies have shown that both complexes are less kinetically inert than the H₄dota complexes, but still much more inert than complexes of open-chain ligands. Nevertheless, the synthesis of ¹⁵³Sm and ¹⁶⁶Ho complexes with this ligand led to stable complexes both in vitro and in vivo. A very low binding of these complexes to hydroxyapatite (HA) and calcified tissues was observed confirming the assumption that a fully ionized phosphonate group(s) is necessary for a strong bone affinity. Both complexes show similar behaviour in vivo and, in general, follow the biodistribution trend of the H₄dota complexes with the same metals.     

Synthesis and fluorescence properties of 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazol derivatives and their terbium complexes

Eight novel 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazol derivatives have been designed and synthesized, and their corresponding Tb³⁺ complexes were also prepared successfully. The fluorescence properties and fluorescence quantum yields of the target complexes were investigated, the results showed that the ligands were an efficient sensitizer for Tb³⁺ luminescence, and the target complexes exhibited characteristic fluorescence emissions of Tb³⁺ ion. The fluorescence intensity of the complex substituted by chlorine was stronger than that of other complexes. The substituents' nature has a great effect upon the electrochemical properties of the target complexes. The results showed that the introduction of the electron‐withdrawing groups tended to decrease the oxidation potential and highest occupied molecular orbital energy levels of the target Tb³⁺ complexes; however, introduction of the electron‐donating groups can increase the corresponding complexes' oxidation potential and highest occupied molecular orbital energy levels. Copyright © 2014 John Wiley & Sons, Ltd.     

Preparation and biological behaviour of some neutral 99mTc-carbonyl dithiocarbamates showing rapid hepatobiliary excretion

A simple procedure for the preparation of ^99mTc—carbonyl complexes of dithiocarbamates in high yield and radiochemical purity has been developed and used for the preparation of ^99mTc—carbonyl complexes of bis(2-hydroxyethyl)dithiocarbamate and bis(2-hydroxypropyl)dithiocarbamate. These complexes were found to be extremely stable and their biological behaviour was studied in mice and compared to that of the ^99mTcN- and the ^99mTc-complexes [prepared by dithionite (dit) reduction] of the same ligands. The carbonyl complexes were found to be efficient hepatobiliary agents and cleared more rapidly than the corresponding ^99mTcN- and ^99mTc(dit)-complexes.     

Antifungal and antitumor activity of heterocyclic thiosemicarbazones and their metal complexes: current status

More than 75 substituted thiosemicarbazones and a number of metal complexes of each have been assayed for their antifungal activity. Their activity is significantly affected by the substituted groups attached at both¹ N and⁴ N of the thiosemicarbazone moiety. Greatest activity occurs for 2-substituted pyridine thiosemicarbazones with differences observed for 2-formylpyridine, 2-acetylpyridine and 2-benzoylpyridine derivatives and their metal complexes. Further, there are activity differences for⁴ N-alkyl-,⁴ N-aryl-,⁴ N-dialkyl- and 3-azacyclothiosemicarbazones and their metal complexes as well as changes in the substituent size among each of these subgroups. Cu(II) complexes are often more active than the uncomplexed thiosemicarbazones, with the latter showing similar activity to Ni(II) complexes in many instances. The reduction potential of the thiosemicarbazone ligand in a Cu(II) complex, the strength of the ligand field and various spectral properties can be correlated to the inhibitory activity.     

Interaction and release of soulble immune complexes from mouse B luymphocytes

Soluble immune complexes (¹²⁵I BSA-anti-BSA-C) bind to B lymphocytes and accumulate at one pole of the cells (“caps”). The complexes remain on the membrane after incubation of the cells at 37 °C in tissue culture medium for several hours. The ¹²⁵I BSA can be quantitatively removed from the cell surface by incubation with excess BSA but not with excess antibody to BSA or preformed BSA-anti-BSA-C complexes. The release of ¹²⁵I BSA is probably due to the removal of the complexes from the cell membrane and not to an exchange between unlabeled BSA in the medium and the labeled BSA present in the membrane-bound complexes. Release of ¹²⁵I BSA by excess BSA is temperature dependent. The membrane-bound complexes can also be removed by incubating the cells with papain fragments of rabbit antibody to mouse Ig (anti-γ₁, γ₂, and k Ig chains). However, after exposure to divalent [F(ab′)² or 7S Ig] rabbit antibodies to mouse Ig, the complexes remain associated with the cells. In addition, after such treatment the complexes cannot be removed by excess BSA or by Fab anti-Ig.     

Red emissive ternary europium complexes: synthesis,optical, and luminescence characteristics

Solid ternary europium complexes consisting of fluorinated β-diketone (thenoyltrifluoroacetone, TTFA) and heteroaromatic bidentate auxiliary ligands were synthesized. The luminescence features of the complexes were estimated using various spectral measurements and clearly proved that the Eu³⁺ ion is efficiently sensitized by ligands by an antenna effect. Photoluminescence excitation spectra have shown that Eu(III) complexes are excited effectively in the ultraviolet (UV) region and the corresponding emission spectra consist of characteristic peaks attributed to the ⁵D₀→⁷F_J transitions of the europium ion with the strongest emission peak at 611 nm (⁵D₀→⁷F₂). From photoluminescence (PL) data, decay time, Judd–Ofelt parameters, transition rates, and quantum efficiency of the complexes were also determined. The Commission Internationale de l'éclairage (CIE) colour coordinates indicated the bright red emission of ternary europium complexes. Correlated colour temperature values indicated the utilization of these complexes in display devices. Judd–Ofelt and photophysical parameters were also estimated theoretically using LUMPAC software. Various frontier molecular orbitals and their respective energy were determined. These red emissive europium complexes could be utilized for fabricating solid-state lighting systems.     

Physical and chemical characterization of soil and poultry litter humic and fulvic metal complexes

Summary Humic and fulvic-zinc complexes obtained from soil and poultry litter were characterized by I.R. spectroscopy, determination of stability constant and the free energy change associated with their formation. Infrared spectroscopy confirmed that both electrovalent, coordinate-covalent bonds of Zn²⁺ with the carboxylate, phenolic hydroxyl and amine groups lead to the formation of their stable complexes. This is evident from the changes in absorption bands at 1700 cm^–1, 1725 cm^–1, 1625 cm^–1 and 1400 cm^–1 of their infrared spectra.The stability constants of complexes are pH-dependent. Interaction of Zn with humic and fulvic acid involved the formation of mononuclear complexes. The values of stability constants of these complexes are lower than those reported earlier.The calculation of the free-energy change associated with salts and complex formation indicates the spontaneity of both reactions, although a higher probability of complex reaction than that of salt formation is evident. The implications of the complexation of metal ions by these naturally occurring polydisperse plyaanions in regulating the movement of metal ions from the ambient soil matrix to plant roots and biological system in terresterial and aquatic environments are indicated.Journal paper no. 2, Department of Soil Science and Agricultural Chemistry, Rajendra Agricultural University, Tirhut College of Agriculture, Dholi, Muzaffarpur, Bihar, India.     

Biological evaluations of newly-designed Pt(II) and Pd(II) complexes using spectroscopic and molecular docking approaches

To perform biological evaluations of newly-designed Pt(II) and Pd(II) complexes, the present study was conducted with targeted protein human serum albumin (HSA) and HCT116 cell line as model of human colorectal carcinoma. The binding of Pt(II) and Pd(II) complexes to HSA was analyzed using fluorescence spectroscopy and molecular docking. The thermal stability and alterations in the secondary structure of HSA in the presence of Pt(II) and Pd(II) complexes were investigated using the thermal denaturation method and circular dichroism (CD) spectroscopy. The cytotoxicity of the Pt(II) and Pd(II) complexes was studied against the HCT116 cell line using MTT assay. The binding analysis revealed that the fluorescence findings were well in agreement with docking results such that there is only one binding site for each complex on HSA. Binding constants of 8.7?×?10³ M^?1, 2.65?×?10³ M^?1, 0.3?×?10³ M^?1, and 4.4?×?10³ M^?1 were determined for Pd(II) and Pt(II) complexes (I–IV) at temperature of 25?°C, respectively. Also, binding constants of 1.9?×?10³ M^?1, 15.17?×?10³ M^?1, 1.9?×?10³ M^?1, and 13.1?×?10³ M^?1 were determined for Pd(II) and Pt(II) complexes (I–IV) at temperature of 37?°C, respectively. The results of CD and thermal denaturation showed that the molecular structure of HSA affected by interaction with Pt(II) and Pd(II) complexes is stable. Cytotoxicity studies represented the growth suppression effect of the Pt(II) and Pd(II) complexes toward the human colorectal carcinoma cell line. Therefore, the results suggest that the new designed Pt(II) and Pd(II) complexes are well promising candidates for use in cancer treatment, particularly for human colorectal cancer.

Communicated by Ramaswamy H. Sarma     

Theoretical insights into the metal chelating and antimicrobial properties of the chalcone based Schiff bases

The emergence of multi-drug resistant pathogens in infectious disease conditions accentuates the need for the design of new classes of antimicrobial agents that could defeat the multidrug resistance problems. As a new class of molecules, the Heterocyclic Schiff base is of considerable interest, owing to their preparative accessibility, structural flexibilities, versatile metal chelating properties, and inherent biological activities. In the present study, CAM-B3LYP/LANL2DZ and M062X/DEF2-TZVP level of density functional method is used to explore the complexation of chalcone based Schiff base derivatives by Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺ metal ions. The HL(1-3)-Co²⁺, HL(1-3)-Ni²⁺ and HL(1-3)-Zn²⁺ complexes formed the distorted tetrahedral geometry. Whereas, the HL(1-3)-Cu²⁺ complexes prefers distorted square-planar geometry. The BSSE corrected interaction energies of the studied complexes reveals that Cu²⁺ ion forms the most stable complexes with all three chalcone based Schiff bases. Of the three Schiff bases studied, the HL2 Schiff base acts as a potent chelating agent and forms the active metal complexes than the HL1 and HL3 Schiff bases. Further, the strength of the interaction follows the order as Cu^2+?>?Ni^2+?>?Co^2+?>?Zn²⁺. The QTAIM analysis reveals that the interaction between the metal ions and coordinating ligand atoms are electrostatic dominant. The metal interaction increases the π-delocalisation of electrons over the entire chelate. Hence, the antimicrobial activity of the metal complexes is more effective than the free Schiff bases. Moreover, the HL(1-3)-Cu²⁺ complexes shows higher antimicrobial activities than the other complexes studied.     

Electronic and molecular structure of M-DNA fragments

To study M-DNA molecular structure (such DNA with transition metal ions placed between the nucleic bases is able to conduct the electric current) and its conductivity mechanisms, we carried out ab initio quantum-mechanical calculations of electronic and spatial structures, thermodynamic characteristics of adenine-thymine (АТ) and guanine-cytosine (GC) base pair complexes with Zn²⁺ and Ni²⁺. To take into account the influence of the alkaline environment, calculations for these complexes were also carried out with hydroxyl and two water molecules. Computations were performed at MP2 level of theory using 6–31+G* basis set. Analogous calculations were carried out for (AC)(TG) stacking dimer of nucleic acid base pairs with two Zn²⁺. The calculation of the interaction energy in complexes has shown the preference of locating the metal ion (instead of the imino proton) between bases in M-DNA. The electronic transition energy calculation has revealed the reduction of the first singlet transition energy in АТ and GC complexes with Ni²⁺ from 4.5 eV to 0.4 - 0.6 eV. Ni²⁺ orbitals take part in the formation of HOMO and LUMO on the complexes investigated. It was shown that charges of metal ions incorporated into complexes with nucleic bases and in dimer decrease significantly.