Isomeric trimethylene and ethylene pendant-armed cross-bridged tetraazamacrocycles and in vitro/in vivo comparisions of their copper(II) complexes

Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as (64)Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing (64)Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to (64)Cu-CB-TR2A (basic ethanol). The in vivo behavior of the (64)Cu complexes was evaluated in normal rats. Rapid and continual clearance of (64)Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to (64)Cu-CB-TE2A. Although (64)Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of (64)Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.     

The stabilities and formation kinetics of some macrocycles with copper(II): crystal structures of some pendant arm macrocycles

Kinetics of complex formation and stability constants of tetra-(2-hydroxpropyl) substituted cyclam (L³) and cyclen (L⁴) with copper(II) have been studied in aqueous solution at room temperature. These data are compared to the corresponding parent compounds (cyclam L¹ and cyclen L²) in an attempt to define the effect of pendant arm upon kinetics and stability constants of the complexes. The kinetics were observed by stopped-flow measurements followed at multiwavelengths. These ligands were chosen to furnish information concerning effect of pendant groups and cavity size on the kinetics and stability of the complexes. Stopped-flow and spectrophotometric titration techniques were used for evaluation of the kinetics and stability constants, respectively. The apparent rate constants increase as CuL³?>?CuL⁴?>?CuL¹?>?CuL². Activation parameters and stability constants of the complexes were estimated. The effect of cavity size on the rate of reaction can be observed in CuL³?>?CuL⁴ and CuL¹?>?CuL² and the effect of pendant groups in CuL³?>?CuL¹ and CuL⁴?>?CuL². Mechanism of the complex formation reaction is proposed. The enhanced stability of the copper(II) complexes formed with L¹ and L² macrocyclic ligands is compared to those formed with analogous pendant arm species.     

Ligand influence on the electrochemical behavior of some copper(II) thiosemicarbazone complexes

The redox properties of the title mono- and binuclear copper(II) chelates have been investigated by cyclic voltammetry in DMF at a working platinum electrode. The cathodic reduction and anodic oxidation of the investigated chelates produced the corresponding electrochemical Cu^I and Cu^IIIspecies stable only in the voltammetric time scale, The effects of substituents on E_1/2, redox properties and stability towards oxidation of the complexes were related to the electron-withdrawing or releasing ability of the substituents on the C=N¹[H, CH₃ or C₆H₅] and/or N⁴H [H, C₂H₅, C₆H₅ or pClC₆H₄] groups, The electron attracting substituents stabilize the Cu(II) complexes while electron-donating groups favor oxidation to Cu(III). Changes in the E_1/2 for the complexes due to remote substituent effects could be related to changes in basicity of N⁴H.Thus, variation in N⁴1-J has more influence on E_1/2 than changes in C=N¹. The correlation between E_1/2 of the complexes and pK_a of the ligands has been attributed to the spherical potential generated by the electron density of the donor atoms at the antibonding d orbitals.     

Detection of unusual lipid mixing in cholesterol-rich phospholipid bilayers: the long and the short of it

Nearest-neighbor recognition studies have revealed that favored sterol-phospholipid associations can be reversed in a fluid bilayer that contains relatively long (high melting) and short (low melting) phospholipids, when the sterol content is sufficiently high; that is, like-lipids now become favored nearest-neighbors. A possible origin of this effect is briefly discussed.     

Synthesis of luminescent homo-dinuclear cationic lanthanide cyclen complexes bearing amide pendant arms through the use of copper catalysed (1,3-Huisgen, CuAAC) click chemistry

The design and synthesis of dinuclear-lanthanide complexes possessing triazole-based bridges, formed by using copper catalysed 1,3-cycloaddition reactions between heptadentate alkyne functionalised cyclen europium or terbium complexes and di-azides (CuAAC reactions), are described. While this click reaction worked well for the formation of the homo-Eu(III) and Tb(III) bis-tri-arm cyclen N,N-dimethyl acetamide complexes, 2Eu and 2Tb, and for the homo-Eu(III) chiral N-methylnaphthalene based complexes 3Eu (S,S,S) and 4Eu (R,R,R), the formation of the Eu(III) complex of the primary amide analogue of 2, namely 1Eu, was not successful, clearly demonstrating the effect that the nature of the pendant arms has on this reaction. Furthermore, the click reactions between the free alkyne cyclen bis-derivatives (5-8) and the di-azide were unsuccessful, most likely due to the high affinity of the cyclen macrocycles for Cu(II). The Eu(III) complexes of 2-4 and 2Tb all gave rise to sensitised metal ion centred emission upon excitation of the triazole or the naphthalene antennae in methanol solution, and their hydration states were determined, which showed that while the Eu(III) mono-nuclear complexes had q ～ 2, the click products all had q ～ 1. In the case of 3Eu (S,S,S) and 4Eu (R,R,R), the circular polarised emission (CPL) was also observed for both, demonstrating the chiral environment of the lanthanide centres.     

Lanthanide-binding peptides with two pendant aminodiacetate arms: impact of the sequence on chelation

Lanthanide complexes with a series of hexapeptides-incorporating two unnatural chelating amino acids with aminodiacetate groups, Ada(1) and Ada(2)-have been examined in terms of their speciation, structure, stability and luminescence properties. Whereas Ada(2) acts as a tridentate donor in all cases, Ada(1) may act as a tetradentate donor thanks to the coordination of the amide carbonyl function assisted by the formation of a six-membered chelate ring. The position of the Ada(1) residue in the sequence is demonstrated to be critical for the lanthanide complex speciation and structure. Ada(1) promotes the coordination of the backbone amide function to afford a highly dehydrated Ln complex and an S-shape structure of the peptide backbone, only when found in position 2.     

In situ selective N-alkylation of pendant pyridyl functionality in mixed-valence copper complexes with methanol and copper(II) bromide

The reactions of CuBr(2) with pyridyl 2,2':6',2'-terpyridine ligands in methanol yielded four copper complexes under solvothermal conditions. The self-assembly processes were accompanied by designing bitopic precursor ligands and increasing the stoichiometric metal-ligand ratio. In the four resulting complexes, the pendant pyridyl groups of pyridylterpyridine were selectively in situ N-methylated and yielded the 4'-(N-methylpyridinium)-2,2':6',2'-terpyridine cations, including the 2-position pyridyl group which is difficult to be N-alkylated due to the steric problem. Partial divalent copper atoms were reduced to cuprous ones in the solvothermal reactions, which made the mixed-valence copper atoms coexist in each compound. The mixed-valence complexes have a varied dimensionality (from 2D to 0D) and the Cu(I)Br cluster, which can be controlled by changing the metal-ligand ratio. Theoretical studies show that the nucleophilic attack of the nitrogen atom in the pendant pyridyl is more facile than others of terpyridine. A possible mechanism was also proposed.     

The electrochemistry of square planar macrocyclic nickel complexes and the reaction of Ni(I) with alkyl bromides: Nickel tetraamine complexes

The electrochemistry of nine cyclic tetraamine complexes of Ni(II) in aprotic solvents has been investigated. It is shown that all form Ni(I) complexes which react with alkyl bromides, but only with some complexes are the reactions catalytic with respect to the nickel complex. The dependence of the electrochemical parameters and the mechanism and kinetics of the coupled chemical reactions on the structure of the ligands are discussed.     

Synthesis and catalytic properties in olefin epoxidation of novel iron(II) complexes with pyridine-containing macrocycles bearing an aminopropyl pendant arm

Three novel iron(II) complexes with pyridine-containing macrocycles bearing an aminopropyl pendant arm were synthesized and characterized. Crystal structures of two of the complexes revealed high-spin iron(II) centers coordinated to the five ligand nitrogen atoms with no coordination of either the solvent molecules or anions, resulting in an unusual square-pyramidal geometry. Related tetradentate ligand CRH formed a low-spin iron(II) complex (meso form was structurally characterized) with a planar arrangement of the four nitrogen atoms from the macrocycle and two axial acetonitrile molecules. Similarly to the corresponding nickel and copper complexes of the pentadentate ligands, the protonation of the amino group on the ligand arm in iron(II) complexes was found to be reversible. Spectral changes and magnetic susceptibility measurements indicated that a change in the geometry and spin state of the metal center is associated with this acid-base process. In the presence of noncoordinating acids (e.g., triflic acid), these complexes, as well as their nonmethylated analogue, can efficiently catalyze the epoxidation of cyclooctene and 1-decene under mild conditions, using hydrogen peroxide as the oxidant. However, in the deprotonated form or in the presence of coordinating acids like HCl, no epoxidation occurs.     

Electrons in fluids: The short and long range interactions

A correlation is presented between the dynamics of electron solvation in alcohols and the long range, polarization po- tential of the same media.     

Mn2+ complexes of 1-oxa-4,7-diazacyclononane based ligands with acetic, phosphonic and phosphinic acid pendant arms: stability and relaxation studies

A new class of macrocyclic ligands based on 1-oxa-4,7-diazacyclononane was synthesized and their Mn(2+) complexes were investigated with respect to stability and relaxation properties. Each ligand has two pendant arms involving carboxylic (H(2)L(1)--1-oxa-4,7-diazacyclononane-4,7-diacetic acid), phosphonic (H(4)L(2)--1-oxa-4,7-diazacyclononane-4,7-bis(methylenephosphonic acid)), phosphinic (H(2)L(3)--1-oxa-4,7-diazacyclononane-4,7-bis(methylenephosphinic acid)) or phenylphosphinic (H(2)L(4)--1-oxa-4,7-diazacyclononane-4,7-bis[methylene(phenyl)phosphinic acid]) acid moieties. H(2)L(3) and H(2)L(4) were synthesized for the first time. The crystal structure of the Mn(2+) complex with H(2)L(4) confirmed a coordination number of 6 for Mn(2+). The protonation constants of all ligands and the stability constants of their complexes with Mn(2+) and some biologically or biomedically relevant metal ions were determined by potentiometry. The protonation sequence of H(2)L(3) was followed by (1)H and (31)P NMR titration and the second protonation step was attributed to the second macrocyclic nitrogen atom. The potentiometric data revealed a relatively low thermodynamic stability of the Mn(2+) complexes with all ligands investigated. For H(2)L(3) and H(2)L(4), full Mn(2+) complexation cannot be achieved even with 100% ligand excess. The transmetallation of MnL(1) and MnL(2) with Zn(2+) was too fast to be followed at pH 6. Variable temperature (1)H NMRD and (17)O NMR measurements have been performed on MnL(1) and MnL(2) to provide information on water exchange and rotational dynamics. The (17)O chemical shifts indicate hydration equilibrium between mono- and bishydrated species for MnL(1), while MnL(2) is monohydrated. The water exchange is considerably faster on MnL(1) (k(ex)(298) = 1.2 × 10(9) s(-1)) than on MnL(2) (k(ex)(298) = 1.2 × 10(7) s(-1)). Small endogenous anions (phosphate, carbonate, citrate) do not replace the coordinated water in either of the complexes, but they induce their slow decomposition. All Mn(2+) complexes are stable toward air-oxidation.     

The influence of molecular weight of the donor polymer on the solid-state behavior of interchain EDA complexes

N-(2-hydroxyethyl)carbazolyl methacrylate (HECM) and N-ethyl-3-hydroxymethyl carbazolyl methacrylate (HMCM-2) were polymerized by group transfer polymerization to varying molecular weights of somewhat narrow molecular weight distribution. The thermal behavior of the homopolymers and of their EDA complexes with poly(β-hydroxyethyl-3,5-dinitrobenzoyl methacrylate) (PDNBM-2) was studied as a function of molecular weight. The T_g′s of both polymers and their miscible complexes increase steadily as molecular weight increases and then become constant at about M _n = 6000. Both the PHECM–PDNBM-2 and PHMCM-2—PDNBM-2 systems are thermally reversible miscible networks over all polymer molecular weights. Miscibility is thermodynamically controlled over the entire range of molecular weights in the first system and decomplexation does not occur below the decomposition temperature. However, miscibility is thermodynamically controlled in the second system when the molecular weight of PHMCM-2 is less than 5000, and kinetically controlled for higher molecular weights. The decomplexation temperature or LCST of the PHMCM-2–PDNBM-2 system occurs below the decomposition temperature and increases with decreasing PHMCM-2 molecular weight, in agreement with theoretical predictions on the dependence of LCST on polymer molecular weight.     

Synthesis, in vitro and in vivo behavior of 188Re(I)-tricarbonyl complexes for the future functionalization of biomolecules

Radiolabeling of biologically active molecules with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺ unit has been of primary interest in recent years. Therefore, we herein report ligands L¹−L⁴ (L¹=histidine, L²=nitrilotriacetic acid, L³=2-picolylamine-N,N-diacetic acid, L⁴=bis(2-pyridymethy)amine) that have been evaluated by radiochemical reactions with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺. These reactions yielded the radioactive complexes of fac-[¹⁸⁸Re(CO)₃L] (L = L¹−L⁴, ¹⁸⁸Re tricarbonyl complexes 1–4), which were identified by HPLC. Complexes 1–4, with log P _o/w values ranging from −2.23 to 2.18, were obtained with yields of ≥95% using ligand concentrations within 10⁻⁶–10⁻⁴M range. Thus, specific activities of 220 GBq/μmol could be achieved. Challenge studies with cysteine and histidine revealed high stability for all of these radioactive complexes, and biodistribution studies in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion occurring primarily through the renal-urinary pathway. In summary, the ligands L¹–L⁴ are potent chelators for the future functionalization of biomolecules labeling with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺.     

Absorption band shape in five-coordinated copper(ii) complexes: influence of the Jahn-Teller effect

A Monte Carlo method has been used to analyze the absorption band shape for A → E electronic transitions, with Jahn-Teller and pseudo-Jahn-Teller interactions included in the Hamiltonian. The results obtained suggest a reconsideration of the assignment of d-d transitions in trigonal bipyramidal copper(II) complexes may be in order.     

The influence of the zwitterionic form on the C=N stretching frequency in nickel and copper complexes of a Schiff base

Summary The Schiff base derived from 2-aminobenzimidazole and salicylaldehyde has been used to prepare a series of nickel(II) and copper(II) complexes. I.r., electronic spectra, elemental analyses, conductivity measurements and magnetic data have been utilized to determine the nature of these complexes.The results show that the base acts as bidentate ligand through the phenolic oxygen and the azomethine nitrogen in the non-polar form of the ligand or the pyridine-like imine nitrogen of imidazole ring in its zwitterionic form.One of the more striking differences between these compounds and those of other Schiffs bases^(1,2) is the coordination spheres of the metal ions with this particular ligand.     

Luminescence and thermal behavior of copper (I) complexes with heterocyclic thiones. Part II: cationic complexes

Copper (I) halide complexes formulated as [(L)₂Cu(μ₂-L)₂Cu(L)₂]²⁺ 2Χ⁻, (X = Cl, Br and L = pyridine-2-thione (py2SH) or 4,6-dimethylpyrimidine-2-thione (dmpymtH)) were prepared, and their photoluminescence and thermal properties were investigated. The complexes are strongly emissive in the solid state, with the emissions being dominated by large Stokes shifts (>200 nm), which are depending on both the heterocyclic thione and the nature of the halogen. These emissions can be assigned to MLCT with some mixing of the halide-to-ligand (XL) CT characters. Simultaneous TG/DTG–DTA technique was used for two complexes with the dmpymtH ligand to determine their thermal degradation, which was found to be very complicated. In inert atmosphere the residues at 1,000 °C (verified with PXRD) were mainly Cu₂S, while at 1,300 °C a mixture of Cu₂S and Cu. In oxygen atmosphere the residues were CuO.     

The preparation of a series of 12-, 13- and 14-membered tetra-imine macrocycles and characterization of their copper(II) complexes

Summary The 12-, 13- and 14-membered tetraphenyl substituted macrocycles Ph₄[12]TIM (2,3,8,9-tetraphenyl-1,4,7,10-tetra-azacyclododeca-1,3,7,9-tetraene), Ph₄[13]TIM (2,3,8,9-tetraphenyl-1,4,7,10-tetra-azacyclotrideca-1,3,7,9-tetraene) and Ph₄[14]TIM (2,3,9,10-tetraphenyl-1,4,8,11-tetradeca-1,3,8,10-tetraene) were prepared and their copper(II) complexes characterised. Magnetic and spectroscopic measurements (i.r. and u.v.-vis.) are discussed. A variety of macrocyclic precursers (KIM = 1,2,8,9-tetraphenyl-3, 7-diaza-2,7-dione) and KIM-dioxime were also prepared and characterised.     

Electrochemical behavior of copper complexes with substituted polypyridinic ligands: an experimental and theoretical study

Experimental redox potentials of the couples [Cu(R-L ( n ))(CH 3CN)] (2+,+), where L (1) is bis-(pyridine-2-ylmethyl)-benzylamine, L (2) is (pyridine-2-ylethyl)(pyridine-2-ylmethyl)-benzylamine, and R is H, Me, or CF 3, were determined in dichloromethane solution. The compounds exhibited one simple quasi-reversible wave over the measured potential range of -500 to +1200 mV, and the E 1/2 values varied from +200 to +850 mV versus SCE. These experimental values were correlated with redox potentials calculated using density functional theory. The optimized geometries and the predicted redox potentials were obtained using the BP86 functional and a combination of the basis sets LACV3P** (for Cu) and cc-pVTZ(-f) (for light atoms). A distortion analysis of all of the optimized geometries for both oxidation states was performed using the generalized interconversion coordinate phi. A linear relation was obtained between this parameter and the redox potentials. However, the [Cu(CF 3-L (1))(CH 3CN)] (+) complex showed the largest deviation, which was explained by the more-rigid structure of the ligand.     

Nickel(II) macrocyclic complexes with long alkyl pendant chain: synthesis,x-ray structure,and anion exchange property in the solid state

A nickel(II) pentaaza macrocyclic complex containing a 1-hexadecyl pendant chain, [Ni(C(25)H(55)N(5))](ClO(4))(2).H(2)O (1), was synthesized by a one-pot metal-template condensation reaction. Crystal data for 1: triclinic, Ponemacr;, a = 8.333(4) A, b = 8.356(3) A, c = 28.374(9) A, alpha = 81.865(19) degrees, beta = 86.242(18) degrees, gamma = 63.871(17) degrees, Z = 2. Solid 1 forms hydrophobic layers that are constructed by the long alkyl chains of the macrocycles. Solid 1 exchanges ClO(4)(-) with NCS(-), PF(6)(-), C(2)O(4)(2-), NO(3)(-), and CF(3)SO(3)(-) that are dissolved in water. From the reaction of [Ni(C(25)H(55)N(5))Cl(2)] with Et(3)NH(TCNQ)(2) in EtOH/DMF/acetone solution, [Ni(C(25)H(55)N(5))(TCNQ)(2)](TCNQ).(CH(3)COCH(3)) (2) (TCNQ = 7,7,8,8-tetracyano-p-quinodimethane) was prepared. Crystal data for 2: triclinic, Ponemacr;, a = 8.459(0) A, b = 13.945 (1) A, c = 26.833(2) A, alpha = 88.744(2) degrees, beta = 84.536(2) degrees, gamma = 80.089(4) degrees, Z = 2. In 2, TCNQ anions coordinate nickel(II) at the axial sites, which form pi-stacked TCNQ(-) dimers to give rise to 1-D chains. The neutral TCNQ molecules are included between the dimerized TCNQ(-) species, which construct a pi-stacked group of six TCNQ units as blocked by the long alkyl chains. Compound 2 is an electric insulator. It shows a weak signal in the EPR spectrum. The magnetic susceptibility data of 2 measured at 5-300 K exhibit a simple paramagnetism at low temperatures (<100 K) but an increase in the magnetic moment at higher temperatures due to the contribution of a thermally accessible triplet state for the antiferromagnetically coupled [TCNQ](2)(2-).