Improved separation scheme for 44Sc produced by irradiation of natCa targets with 12.8 MeV protons.

INTRODUCTION: 44Sc is of great interest as a positron emission tomography (PET) radionuclide due to its suitable nuclear characteristics: Eß+max = 1.47 MeV, branching ratio 94.3% and convenient half-life of 3.97 h. Here, 44Sc was produced via the widely used reaction 44Ca (p,n)44Sc using natural calcium as a target. METHODS: The irradiation was performed at TRIUMF using the 13 MeV cyclotron. The separation consisted of a combination of DGA branched resin and Dowex 50Wx8 (200-400 mesh). The distribution coefficients of Sc3+ on Dowex 50Wx8 (NH4+ form, 200-400 mesh) with ammonium α-hydroxyisobutyrate (pH = 4.8) medium were determined in this study. RESULTS AND CONCLUSION: The tested scheme allows both a reliable separation of 44Sc from the target material as well as from the other competitive metals and a final fraction with high specific activity. The achieved radiochemical yield was 95 ± 3%.

La(iii) biodistribution profiles from intravenous and oral dosing of two lanthanum complexes, La(dpp)3 and La(XT), and evaluation as treatments for bone resorption disorders.

Trivalent lanthanum (La3+) has the potential to treat bone resorption disorders (such as osteoporosis) by eliciting a bone-building response in the cells which control skeletal remodelling. Because La3+ suffers from extremely poor intestinal absorption, specifically designed chelators are required in order that a biologically active form of lanthanum can be administered orally. Two such chelators, 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdpp) and bis-{[bis(carboxymethyl)amino]methy}phosphinic acid (H5XT), have previously been the subjects of extensive physical, in vitro, and in vivo testing as the tris- and mono-lanthanum(iii) complexes La(dpp)3 and La(XT), respectively. In this manuscript, we expand upon those studies to include 4-week intravenous (IV) and oral La3+ biodistribution profiles, which show that the metal ion initially accumulates in the liver followed by preferential redistribution and retention by bone. Of the two compounds, La(XT) demonstrates the more favourable in vivo characteristics, therefore dose-dependent oral biodistribution studies were carried out with this complex. These show drug saturation above a dose of 100 mg kg-1 day-1, so liver histology was performed in order to assess any potential toxicity. Finally, we improve upon the physical characterization of La(dpp)3 to include a single crystal X-ray structure, which exhibits an 8-coorindate La3+ centre with two bound water molecules, and a disordered exoclathrate-type hydrogen bonded network.

Harnessing the bone-seeking ability of Ca(II)-like metal ions in the treatment of metastatic cancer and resorption disorders.

Metal ions are naturally retained by skeletal tissues in living systems because of their high affinity for the hydroxyapatite-like mineral matrix that makes up cortical bone. This is particularly true for metal ions that bear a close resemblance to calcium(ii) (such as the lanthanides or alkaline earth metals), and in a few key cases this targeting ability has been exploited in order to develop medicinal agents that are intended to treat bones which have become diseased. In this review, we focus on two areas where this has been particularly effective: first is in the diagnosis and therapy of metastatic bone cancer, in which radioactive metal ions including (99m)Tc, (153)Sm, and (223)Ra are used to image, alleviate, and ablate harmful cancerous legions with good specificity versus healthy tissues; second is the use of trivalent lanthanides to treat osteoporosis, an emerging concept which has gathered significance over the last 15 years, and is now entering preclinical trials with carefully designed systems.

Exploring the potential of gold(III) cyclometallated compounds as cytotoxic agents: variations on the C

A series of novel (C^N) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)L(1)L(2)](n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.

In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders.

Bone density diseases such as osteoporosis affect a significant number of people worldwide. Lanthanide ions are functional mimics of calcium ions, able to substitute for Ca2+ in the bone mineral component, hydroxyapatite (HAP). Bone undergoes a continuous remodelling cycle and lanthanides can affect this cycle, exerting a positive influence on bone mineral. We have been engaged in efforts to find new lanthanide containing complexes as active agents for treatment of these diseases and have identified two lead compounds, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Hdpp) and a phosphinate-EDTA derivative, bis[[bis(carboxymethyl)amino]-methyl]phosphinate (H5XT). In this paper, we report in vivo data for the first time for the two lead compounds. The pharmacokinetics of La(dpp)3 suggest the complex is rapidly cleared from plasma. We demonstrate that La3+ accumulates in the bone following IV dose of either La(dpp)3 or La(XT) and we have investigated the influence of each chelating ligand on the incorporation of La3+ into HAP using ITC and HAP-binding studies.

Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models.

Alzheimer's disease (AD) is a neurological disease of confusing causation with no cure or prevention available. The definitive diagnosis is made postmortem, in part through the presence of amyloid-beta plaques in the brain tissue, which can be done with the small molecule thioflavin-T (ThT). Plaques are also found to contain elevated amounts of metal ions Cu(ii) and Zn(ii) that contribute to the neurotoxicity of amyloid-beta (Aß). In this paper, we report in silico, in vitro, and ex vivo studies with ThT-derived metal binders 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT) and their respective iodinated counterparts, HBXI and HBTI. They exhibit low cytotoxicity in a neuronal cell line, potential blood-brain barrier penetration, and interaction with Aß fibrils from senile plaques present in human and transgenic mice AD models. Molecular modelling studies have also been undertaken to understand the prospective ligand-Aß complexes as well as to rationalize the experimental findings. Overall, our studies demonstrate that HBX, HBT, HBXI, and HBTI are excellent agents for future use in in vivo models of AD, as they show in vitro efficacy and biological compatibility. In addition to this, we present the glycosylated form of HBX (GBX), which has been prepared to take advantage of the benefits of the prodrug approach. Overall, the in vitro and ex vivo assays presented in this work validate the use of the proposed ThT-based drug candidate series as chemical tools for further in vivo development.

Unprecedented sugar-dependent in vivo antitumor activity of carbohydrate-pendant cis-diamminedichloroplatinum(II) complexes.

Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.

[ReO(N2O2)X] complexes: "4 + 1"?

[ReO(ppme)X] (where ppme(2-) is 2,5-diazo-N,N'-dimethylhexyl-1,6-bis(phenylphosphinate), X = Br0.3Cl0.7) has been synthesized via a substitution reaction and structurally characterized. The coordination geometry is a distorted octahedron and one phosphinate coordinates cis and the other trans to the oxo O atom. This coordination mode is conserved in all [ReOppmeX] complexes synthesized in this study. [ReO(ppme)Cl] has been prepared by a reduction/complexation reaction from [NH4][ReO4]. [ReO(ppme)Cl] reacts with thiocyanate and benzene thiolate forming [ReO(ppme)X] (X = (-)NCS, (-)SC6H5), but the one-pot synthesis of the respective ternary thiolate complexes from perrhenate was not successful. The reduction/complexation reaction of a thiol, H2ppmeCl4, and perrhenate resulted in the formation of [H3ppme][ReO(SR)4], the reaction of which with [ReO(ppme)Cl] does not lead to [ReO(ppme)SR] in high yields.

Insulin-enhancing vanadium(III) complexes.

Simple, high-yield, large-scale syntheses of the V(III) complexes tris(maltolato)vanadium(III), V(ma)3, tris(ethylmaltolato)vanadium(III), V(ema)3, tris(kojato)vanadium(III) monohydrate, V(koj)3-H2O, and tris(1,2-dimethyl-3-hydroxy-4-pyridinonato)vanadium(III) dodecahydrate, V(dpp)3-12H2O, are described; the characterization of these complexes by various methods and, in the case of V(dpp)3-12H2O, by an X-ray crystal structure determination, is reported. The ability of these complexes to normalize glucose levels in the STZ-diabetic rat model has been examined and compared with that of the benchmark compound BMOV (bis(maltolato)oxovanadium(IV)), an established insulin-enhancing agent.

Lanthanide chemistry with (bis[[bis(carboxymethyl)amino]methyl]phosphinate: what does an extra phosphinate group do to EDTA?

H5XT (bis[[bis(carboxymethyl)amino]methyl]phosphinic acid) is an EDTA(4-)-like ligand containing an extra phosphinate group. [Co(II)(XT)]3-, [Co(III)(XT)]2-, and a series of [Ln(XT)]2- complexes have been prepared. The phosphinate group is not coordinated in the Co complexes but is bound in the lanthanide complexes. Solid state and solution behaviors of Ln-XT species are consistent: both monoprotonated and nonprotonated species have been found. Protonation of the metal complex does not lead to dissociation of a carboxylate; rather, the proton distributes around the molecular ion. The pM values of Ln-XT are comparable to those of Ln-EDTA but are higher than those of Ln-TMDTA. The inclusion of a phosphinate eases the selectivity of an EDTA-type ligand for late lanthanides.

Sugar-pendant diamines.

A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).

Chemistry of re with N,N'-bis(2-pyridylmethyl)ethylenediamine (H2pmen): hydrolysis, dehydrogenation, and ternary complexes.

A number of Re complexes with N,N'-bis(2-pyridylmethyl)ethylenediamine (H2pmen) have been made from [NH4][ReO4]. [ReOCl2(H2pmen)]Cl, [ReOCl(Hpmen)][ReO4], and [ReO2(H2pmen)][ReO4] are related by hydrolysis/HCl substitution. [ReOCl(Hpmen)][ReO4] was structurally characterized and found to contain a water-stable amido-Re bond. Dehydrogenation of the N-donor ligand from each amine to imine with concomitant two-electron reduction of the Re center occurs readily in these systems. With suitable 3-hydroxy-4-pyrones, ternary complexes such as [ReIIICl(ma)(C14H14N4)][ReO4].CH3OH, 5, were made from [NH4][ReO4], H2pmen.4HCl and pyrones in one-pot syntheses. 5, a seven-coordinate ReIII complex, was structurally characterized.

Effects of sequential replacement of -NH2 by -OH in the tripodal tetraamine tren on its acidity and metal ion coordinating properties.

The preparation is described of two modified derivatives of the tripodal tetraamine tren, 2-hydroxy-N,N-bis(2-aminoethyl)ethylamine, NN(2)O222, and 2-amino-N,N-bis(2-hydroxyethyl)ethylamine, NNO(2)222, in which one and two primary amines, respectively, have been replaced with hydroxyl groups. The aqueous acid-base and metal ion (Ni2+, Cu2+, Zn2+) coordination properties of these two compounds were studied by potentiometric, spectrophotometric, and NMR titrations. Two and three acidity constants, respectively, were determined for NNO(2)222 and NN(2)O222 by potentiometry. NMR titrations proved that deprotonation of the two OH residues in NNO(2)222, and of the one in NN(2)O222, corresponded to pK(a) > 14. Acidity constants related to deprotonation of the terminal primary amine functions were similar in both NNO(2)222 and NN(2)O222 (and to those in the parent compound tren), whereas deprotonation of the tertiary ammonium N atom had a very different acidity constant in each of these three compounds. Charge repulsion, polar effects, and intramolecular hydrogen bond formation are responsible for the discrepancy. Chelated diamine metal complexes for each ligand studied depended only on the basicity of the corresponding two amines, suggesting that the hydroxyl group interacted with the metal ion very weakly in acidic or neutral solutions. The ML2+ species further deprotonated to form M(L - H)+ and M(L - 2H) complexes, in which the protons are released from the coordinated OH group. A pM vs pH correlation showed that replacing an NH2 group with a OH group in tren or NN(2)O222 makes the resulting metal complex less stable. Electronic spectra showed that the Cu(II) complexes of both NNO(2)222 and NN(2)O222 adopted a square pyramidal geometry rather than a trigonal bipyramidal geometry. The X-ray crystal structure analysis of the zinc complex [Zn(OH)(mu-NNO(2)222 - H)Zn(NNO(2)222)]2+, as its [BF4]- salt, shows a dinuclear molecule containing two zinc ions, each coordinated in a distorted trigonal bipyramid. The coordination environment at one zinc atom is composed of the four donor groups of a mono-O-deprotonated ligand NNO(2)222 and a hydroxyl ion with the central nitrogen atom of the ligand and the hydroxyl ion in equatorial positions. The oxygen atom of the deprotonated alkoxo group bridges to the second zinc atom, which is coordinated by this atom and one undeprotonated ligand NNO(2)222.

Seven-coordinate [ReVON4X2]+ complexes (X = O and Cl).

The oxorhenium(V) complexes with ligands containing N4 (H2pmen) and N4O2 (H2bbpen, H2Clbbpen, and H2bped) donor atom sets have been synthesized. X-ray crystallographic analyses of the [ReO(H2pmen)Cl2]+, [ReO(bbpen)]+, and [ReO(bped)]+ complexes showed that all three cations share a rare seven-coordinate structure with a distorted pentagonal bipyramidal geometry, which represents a novel and potentially general structural motif in ReV = O complexes. 1H NMR spectroscopy shows that the structures of the complexes are retained in the solution.

Homotrinuclear lanthanide(III) arrays: assembly of and conversion from mononuclear and dinuclear units.

The reactions of potentially hexadentate H2bbpen (N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)-ethylenediamine, H2L1), H2(Cl)bbpen (N,N'-bis(5-chloro-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine, H2L2), and H2(Br)bbpen (N,N'-bis(5-bromo-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine, H2L3) with Ln(III) ions in the presence of a base in methanol resulted in three types of complexes: neutral mononuclear ([LnL(NO3)]), monocationic dinuclear ([Ln2L2(NO3)]+), and monocationic trinuclear ([Ln3L2(X)n(CH3OH)]+), where X = bridging (CH3COO-) and bidentate ligands (NO3-, CH3COO-, ClO4-) and n is 4. The formation of a complex depends on the base (hydroxide or acetate) and the size of the respective Ln(III) ion. All complexes were characterized by infrared spectroscopy, mass spectrometry, and elemental analyses; in some cases, X-ray diffraction studies were also performed. The structures of the neutral mononuclear [Yb(L1)(NO3)], dinuclear [Pr2(L1)2(NO3)(H2O)]NO3.CH3OH and [Gd2(L1)2(NO3)]NO3.CH3OH.3H2O, and trinuclear [Gd3(L3)2(CH3COO)4(CH3OH)]ClO4.5CH3OH and [Sm3(L1)2(CH3COO)2(NO3)2(CH3OH)]NO3.CH3OH.3.65H2O were solved by X-ray crystallography. The [LnL(NO3)] or [Ln2L2(NO3)]+ complexes could be converted to [Ln3L2(X)n(CH3OH)]+ complexes by the addition of 1 equiv of a Ln(III) salt and 2-3 equiv of sodium acetate in methanol. The trinuclear complexes were found to be the most stable of the three types, which was evident from the presence of the intact monocationic high molecular weight parent peaks ([Ln3L2(X)n]+) in the mass spectra of all the trinuclear complexes and from the ease of conversion from the mononuclear or dinuclear to the trinuclear species. The incompatibility of the ligand denticity with the coordination requirements of the Ln(III) ions was proven to be a useful tool in the construction of multinuclear Ln(III) metal ion arrays.

Coaggregation of paramagnetic d- and f-block metal ions with a podand-framework amine phenol ligand.

This report covers initial studies in the coaggregation of nickel (Ni2+) and lanthanide (Ln3+) metal ions to form complexes with interesting structural and magnetic properties. The tripodal amine phenol ligand H3tam (1,1,1-tris(((2-hydroxybenzyl)amino)methyl)ethane) is shown to be particularly accommodating with respect to the geometric constraints of both transition and lanthanide metal ions, forming isolable complexes with both of these ion types. In the solid-state structure of [Ni(H2tam)(CH3CN)]PF6.2.5CH3CN.0.5CH3OH (1), the Ni(II) center has a distorted octahedral geometry, with an N3O2 donor set from the [H2tam]- ligand and a coordinated solvent (acetonitrile) occupying the sixth site. The reaction of stoichiometric amounts of H3tam with the Ni(II) ion in the presence of lanthanide(III) ions provides [LnNi2(tam)2]+ cationic complexes which contain coaggregated metal ions. These complexes are isolable and have been characterized by a variety of analytical techniques, with mass spectrometry proving to be particularly diagnostic. The solid-state structures of [LaNi2(tam)2(CH3OH)1/2(CH3CH2OH)1/2(H2O)]ClO4.0.5CH3OH.0.5CH3CH2OH.4H2O (2), [DyNi2(tam)2(CH3OH)(H2O)]ClO4.CH3OH. H2O(6), and [YbNi2(tam)2(H2O)]ClO4.2.58H2O(9) have been determined. Each complex contains two octahedral Ni(II) ions, each of which is encapsulated by the ligand tam3- in an N3O3 coordination sphere; each [Ni(tam)]-unit caps the lanthanide(III) ion via bridging phenoxy oxygen donor atoms. In 2, La3+ is eight-coordinated, while in 6, Dy(III) is seven- (to "weakly eight-") coordinated, and Yb(III) in 9 has a six-coordination environment. The complexes are symmetrically different, 2 possessing C2 symmetry and 6 and 9 having C1 symmetry. Magnetic studies of 2, 6, and 9 indicate that antiferromagnetic exchange coupling between the Ni(II) and Ln(III) ions increases with decreasing ionic radius of Ln(III).

Vanadyl-biguanide complexes as potential synergistic insulin mimics.

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big)2], bis(N'N'-dimethylbiguanidato)oxovanadium(IV), [VO(metf)2], and bis(beta-phenethyl-biguanidato)oxovanadium(IV), [VO(phenf)2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf)2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf)2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf)2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg-1 i.p. and 0.60 mmol kg-1 p.o. (previously established as ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.

Active oxygen species formation in synaptosomes exposed to an aluminum chelator.

This study evaluates the potential of two chelators, 1,2-dimethyl-3-hydroxypyridine-4-one (Hdpp) and 1-n-butyl-2-methyl-3-hydroxypyridin-4-one (Hnbp), to modulate cerebral rates of free radical production. The fluorometric assay for 2',7'-dichlorofluorescein, which is formed by oxidation of a nonfluorescent precursor (2',7'-dichlorofluorescein diacetate), was used to assay reactive oxygen species (ROS) production. The chelator Hdpp alone and the aluminum complexes of each chelator, Al (dpp)3 and Al (nbp)3, all inhibited basal rates of generation of ROS within a rat cerebral synaptosomal fraction. In the presence of an iron salt (1 microM FeSO4), a major enhancement of synaptosomal ROS formation was apparent. However, with the addition of an equimolar concentration of Hdpp, Al(dpp)3, or Al(nbp)3, this stimulation was completely abolished. The N-substituted-3-hydroxy-4-pyridinones have been proposed to be of clinical utility for the removal of iron or aluminum from tissues. The clinical potential of this class of chelator may be enhanced by their ability to inhibit iron-related oxidative events.