Gadolinium(III) 1,2-hydroxypyridonate-based complexes: toward MRI contrast agents of high relaxivity

Prospective gadolinium(III) MRI contrast agent precursors [Gd-TREN-1,2-HOPO] (1) [TREN-1,2-HOPO = tris[(1-hydroxy-2-oxo-1,2-dihydropyridine-6-carboxamido)ethyl]amine] and [Gd-TREN-bis(Me-3,2-HOPO)-1,2-HOPO] (2) have been synthesized and characterized by relaxometric measurements. The water proton relaxivity values of 1 and 2 (20 MHz and 25 degrees C) are 9.5 and 9.3 mM(-)(1)s(-)(1), respectively, suggesting the presence of two coordinated water molecules. The molecular structure of [1.DMF](2) was obtained and reveals a similar eight-coordinate geometry to [Gd-TREN-Me-3,2-HOPO.2H(2)O] ([3.2H(2)O]). A shape analysis of the coordination polyhedron of 1 reveals that this geometry is best described as a bicapped trigonal prism, poised to accommodate an additional donor atom to give a tricapped trigonal prismatic intermediate. This geometry supports the model that formation of a tris-aquo intermediate for 1 enables fast and associative water exchange.     

Synthesis of homochiral tris(2-alkyl-2-aminoethyl)amine derivatives from chiral alpha-amino aldehydes and their application in the synthesis of water soluble chelators

A novel synthesis of 3-fold symmetric, homochiral tris(2-alkyl-2-aminoethyl)amine (TREN) derivatives is presented. The synthesis is general in scope, starting from readily prepared chiral alpha-amino aldehydes. The optical purity of the N-BOC protected derivatives of tris(2-methyl-2-aminoethyl)amine and tris(2-hydroxymethyl-2-aminoethyl)amine has been ascertained by polarimetry and chiral NMR chemical shift experiments. An X-ray diffraction study of the L-alanine derivative (tris(2-methyl-2-aminoethyl)amine.3 HCl, L-Ala(3)-TREN) is presented: crystals grown from ether diffusion into methanol are cubic, space group P2(1)3 with unit cell dimensions a = 11.4807(2) A, V = 1513.23(4) A(3), and Z = 4. Attachment of the triserine derived backbone tris(2-hydroxymethyl-2-aminoethyl)amine (L-Ser(3)-TREN) to three 3-hydroxy-1-methyl-2(1H)-pyridinonate (3,2-HOPO) moieties, followed by complexation with Gd(III) gives the complex Gd(L-Ser(3)-TREN-Me-3,2-HOPO)(H(2)O)(2), which is more water soluble than the parent Gd(TREN-Me-3,2-HOPO)(H(2)O)(2) and a promising candidate for magnetic resonance imaging (MRI) applications. Crystals of the chiral ferric complex Fe(L-Ser(3)-TREN-Me-3,2-HOPO) grown from ether/methanol are orthorhombic, space group P2(1)2(1)2(1), with unit cell dimensions a = 13.6290(2) A, b = 18.6117(3) A, c = 30.6789(3) A, V = 7782.0(2) A(3), and Z = 8. The solution conformation of the ferric complex has been investigated by circular dichroism spectroscopy. The coordination chemistry of this new ligand and its iron(III) and gadolinium(III) complexes has been studied by potentiometric and spectrophotometric methods. Compared to the protonation constants of previously studied polydentate 3,2-HOPO-4-carboxamide ligands, the sum of protonation constants (log beta(014)) of L-Ser(3)-TREN-Me-3,2-HOPO (24.78) is more acidic by 1.13 log units than the parent TREN-Me-3,2-HOPO. The formation constants for the iron(III) and gadolinium(III) complexes have been evaluated by spectrophotometric pH titration to be (log K) 26.3(1) and 17.2(2), respectively.     

Syntheses and relaxation properties of mixed gadolinium hydroxypyridinonate MRI contrast agents

The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2- didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 degrees C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5-4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (< 100 ns), higher molecular weights (> 700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1: Z = 4, a = 15.6963(2) A, b = 16.9978(1) A, c = 17.1578(2) A, alpha = 61.981(1) degrees, beta = 75.680(1) degrees, gamma = 71.600(1) degrees), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.     

Hexadentate hydroxypyridonate iron chelators based on TREN-Me-3,2-HOPO: variation of cap size

TREN-Me-3,2-HOPO, TR322-Me-3,2-HOPO, TR332-Me-3,2-HOPO, and TRPN-Me-3,2-HOPO correspond to stepwise replacement of ethylene by propylene bridges. A series of tripodal, hexadentate hydroxypyridinone ligands are reported. These incorporate 1-methyl-3,2-hydroxypyridinone (Me-3,2-HOPO) bidentate chelating units for metal binding. They are varied by systematic enlargement of the capping scaffold which connects the binding units. The series of ligands and their iron complexes are reported. Single crystal X-ray structures are reported for the ferric complexes of all four tripodal ligands: FeTREN-Me-3,2-HOPO.0.375C(4)H(10)O.0.5CH(2)Cl(2) [P2(1)/n (No. 14), Z = 8, a = 20.478(3) A, b = 12.353(2) A, c = 27.360(3) A; beta = 91.60(1) degrees ]; FeTR322-Me-3,2-HOPO.CHCl(3).0.5C(6)H(14).CH(3)OH.0.5H(2)O [P2(1)/n (No. 14), Z = 4, a = 12.520(3) A, b = 22.577(5) A, c = 16.525(3) A; beta = 111.37(3) degrees ]; FeTR332-Me-3,2-HOPO.3.5CH(3)OH [C2/c (No. 15), Z = 8, a = 13.5294(3) A, b = 19.7831(4) A, c = 27.2439(4) A; beta = 101.15(3) degrees ]; FeTRPN-Me-3,2-HOPO.C(3)H(7)NO.2C(4)H(10)O [P1 (No. 2), Z = 2, a = 11.4891(2) A, b = 12.3583(2) A, c = 15.0473(2) A; alpha = 86.857(1) degrees, beta = 88.414(1) degrees, gamma = 70.124(1) degrees ]. The structures show the importance of intermolecular hydrogen bonds and the effect of cap enlargement to the stability and geometry of the metal complexes throughout the series. All protonation and iron complex formation constants have been determined from solution thermodynamic studies. The TREN-capped derivative is the most acidic, with a cumulative protonation constant, log beta(014), of 25.95. Corresponding values of 26.35, 26.93, and 27.53 were obtained for the TR322, TR332, and TRPN derivatives, respectively. The protonation constants and NMR spectroscopic data are interpreted as being due to the influence of specific hydrogen-bond interactions. The incremental enlargement of ligand size results in a decrease in iron-chelate stability, as reflected in the log beta(110) values of 26.8, 26.2, 26.42, and 24.48 for the TREN, TR322, TR332, and TRPN derivatives, respectively. The metal complex formation constants are also affected by the acidity of a proximal (non-metal-binding) amine in the complexes, a trend consistent with the effects of internal hydrogen bonding. The ferric complexes display reversible reduction potentials (measured relative to the normal hydrogen electrode (NHE)) between -0.170 and -0.223 V.     

Thorium(IV) complexes of bidentate hydroxypyridinonates

The coordination chemistry of actinide(IV) ions with hydroxypyridinone ligands has been initially explored by examining the complexation of Th(IV) ion with bidentate PR-1,2-HOPO (HL(1)()), PR-Me-3,2-HOPO (HL(2)()), and PR-3,4-HOPO-N (HL(3)()) ligands. The complexes Th(L(1)())(4), Th(L(2)())(4), and Th(L(3)())(4) were prepared in methanol solution from Th(acac)(4) and the corresponding ligand. Single-crystal X-ray diffraction analyses are reported for the free ligand PR-Me-3,2-HOPO (HL(2)()) [Ponemacr;, Z = 8, a = 8.1492(7) A, b = 11.1260(9) A, c = 23.402(2) A, alpha = 87.569(1) degrees, beta = 86.592(1) degrees, gamma = 87.480(1) degrees ], and the complex Th(L(2)())(4).H(2)O [Pna2(1) (No. 33), Z = 4, a = 17.1250(5) A, b = 12.3036(7) A, c = 23.880 (1) A]. A comparison of the structure of the metal complex Th-PR-Me-3,2-HOPO with that of free ligand PR-Me-3,2-HOPO reveals that the ligand geometry is the same in the free ligand and in the metal complex. Amide hydrogen bonds enhance the rigidity and stability of the complex and demonstrate that the Me-3,2-HOPO ligands are predisposed for metal chelation. Solution thermodynamic studies determined overall formation constants (log beta(140)) for Th(L(1)())(4), Th(L(2)())(4), and Th(L(3)())(4) of 36.0(3), 38.3(3), and 41.8(5), respectively. Species distribution calculations show that the 4:1 metal complex Th(L)(4) is the dominant species in the acidic range (pH < 6) for PR-1,2-HOPO, in weakly acidic to physiological pH range for PR-Me-3,2-HOPO and in the high-pH range (>8) for PR-3,4-HOPO-N. This finding parallels the relative acidity of these structurally related ligands. In the crystal of [Th(L(2)())(4)].H(2)O, the chiral complex forms an unusual linear coordination polymer composed of linked, alternating enantiomers.     

The effect of ligand scaffold size on the stability of tripodal hydroxypyridonate gadolinium complexes

The variation of the size of the capping scaffold which connects the hydroxypyridonate (HOPO) binding units in a series of tripodal chelators for gadolinium (Gd) complexes has been investigated. A new analogue of TREN-1-Me-3,2-HOPO (1) (TREN = tri(ethylamine)amine) was synthesized: TREN-Gly-1-Me-3,2-HOPO (2) features a glycine spacer between the TREN cap and HOPO binding unit. TRPN-1-Me-3,2-HOPO (3) has a propylene-bridged cap, as compared to the ethylene bridges within the TREN cap of the parent complex. Thermodynamic equilibrium constants for the acid-base properties of 2 and the Gd(3+) complexation strength of 2 and 3 were measured and are compared with that of the parent ligand. The most basic ligand is 2 while 3 is the most acidic. Both 2 and 3 form Gd(3+) complexes of similar stability (pGd = 16.7 and 15.6, respectively) and are less stable than the parent complex Gd-1 (pGd = 19.2). Two of the three complexes are more stable than the bis(methylamide)diethylenetriamine pentaacetate complex Gd(DTPA-BMA) (pGd = 15.7) while the other is of comparable stability. Enlargement of the ligand scaffold decreases the stability of the Gd(3+) complexes and indicates that the TREN scaffold is superior to the TRPN and TREN-Gly scaffolds. The proton relaxivity of Gd-2 is 6.6 mM(-)(1) s(-)(1) (20 MHz, 25 degrees C, pH 7.3), somewhat lower than the parent Gd-1 but higher than that of the MRI contrast agents in clinical practice. The pH-independent relaxivity of Gd-2 is uncharacteristic of this family of complexes and is discussed.     

Plutonium(IV) sequestration: structural and thermodynamic evaluation of the extraordinarily stable cerium(IV) hydroxypyridinonate complexes

Ligands containing the 1-methyl-3-hydroxy-2(1H)-pyridinone group (Me-3,2-HOPO) are powerful plutonium(IV) sequestering agents. The Ce(IV) complexes of bidentate and tetradentate HOPO ligands have been quantitatively studied as models for this sequestration. The complexes Ce(L1)4, Ce(L2)4, Ce(L3)2, and Ce(L4)2 (L1 = Me-3,2-HOPO; L2 = PR-Me-3,2-HOPO; L3 = 5LI-Me-3,2-HOPO; L4 = 5LIO-Me-3,2-HOPO) were prepared in THF solution from Ce(acac)4 and the corresponding ligand. The complex Ce(L4)2 was also prepared in aqueous solution by air oxidation of the Ce(III) complex [Ce(L4)2]-. Single-crystal X-ray diffraction analyses are reported for Ce(L1)(4)x2CHCl3 [P1 (no. 2), Z = 2, a = 9.2604(2) A, b = 12.1992(2) A, c = 15.9400(2) A, alpha = 73.732(1) degrees, beta = 85.041(1) degrees, gamma = 74.454(1) degrees], Ce(L3)2x2CH3OH [P2(1)/c (no. 14), Z = 4, a = 11.7002(2) A, b = 23.0033(4) A, c = 15.7155(2) A, beta = 96.149(1) degrees], Ce(L4)(2).2CH3OH [P1 (no. 2), Z = 2, a = 11.4347(2) A, b = 13.8008(2) A, c = 15.2844(3) A, alpha = 101.554(1) degrees, beta = 105.691(1) degrees, gamma = 106.746(1) degrees], and Ce(L4)2x4H2O [P2(1)/c (no. 14), Z = 4, a = 11.8782(1) A, b = 22.6860(3) A, c = 15.2638(1) A, beta = 96.956(1) degrees]. A new criterion, the shape measure S, has been introduced to describe and compare the geometry of such complexes. It is defined as [formula: see text], where m is the number of edges, delta i is the observed dihedral angle along the ith edge of delta (angle between normals of adjacent faces), theta i is the same angle of the corresponding ideal polytopal shape theta, and min is the minimum of all possible values. For these complexes the shape measure shows that the coordination geometry is strongly influenced by small changes in the ligand backbone or solvent. Solution thermodynamic studies determined overall formation constants (log beta) for Ce(L2)4, Ce(L3)2, and Ce(L4)2 of 40.9, 41.9, and 41.6, respectively. A thermodynamic cycle has been used to calculate these values from the corresponding formation constants of Ce(III) complexes and standard electrode potentials. From the formation constants and from the protonation constants of the ligands, extraordinarily high pM values for Ce(IV) are generated by these tetradentate ligands (37.5 for Ce(L3)2 and 37.0 for Ce(L4)2). The corresponding constants for Pu(IV) are expected to be substantially the same.     

Terephthalamide-containing analogues of TREN-Me-3,2-HOPO

A series of terephthalamide-containing analogues based on TREN-Me-3,2-HOPO have been prepared. These analogues contain one, two, or three bidentate 2,3-dihydroxyterephthalamide (TAM) units in place of the 3,2-hydroxypyridinone (HOPO) units on the parent hexadentate ligand. One representative ligand in the series, TRENHOPOTAM2, and its gallium complex have been structurally characterized by X-ray diffraction. TRENHOPOTAM2 crystallizes in the monoclinic space group P2(1)/c with cell parameters a = 16.0340(17) A, b = 17.0609(18) A, c = 16.0695(17) A, beta = 113.837(2) degrees, and Z = 4. Ga[TRENHOPOTAM2] also crystallizes in the monoclinic space group P2(1)/c, with cell parameters a = 16.3379(14) A, b = 15.2722(13) A, c = 19.4397(17) A, beta = 91.656(2) degrees, and Z = 4. The conformation of the TRENHOPOTAM2 ligand structure suggests that the ligand is predisposed for metal ion binding. The aqueous protonation and ferric ion coordination chemistry of all ligands in the series were examined using potentiometric and spectrophotometric methods, giving log formation constants of 34.6(2) (beta110) and 38.8(2) (beta111) for the ferric TRENHOPO2TAM complexes, 41.0(3) (beta110) and 45.4(3) (beta111) for the ferric TRENHOPOTAM2 complexes, and 45.2(2) (beta110) and 50.9(2) (beta111) for the ferric TRENTAM3 complexes. These thermodynamic data confirm that adding terephthalamide units to a hydroxypyridinone-containing ligand tends to increase the stability of the resulting iron complex. The ferric TRENTAM3 complex is one of the most stable iron complexes yet reported.     

The study of complex equilibria of uranium(VI) with selenate

Uranyl (M)-selenate (L) complex equilibria in solution were investigated by spectrophotometry in visible range and potentiometry by means of uranyl ion selective electrode. The formation ML and ML(2) species was proved and the corresponding stability constants calculated were: log beta(1) = 1.57(6) +/- 0.01(6), log beta(2) = 2.42(3) +/- 0.01(3) (I = 3.0 mol 1(-1) Na(ClO(4), SeO(4)) (spectrophotometry) at 298.2 K. Using potentiometry the values for infinite dilution (I --> 0 mol 1(-1)) were: log beta(1) = 2.64 +/- 0.01, log beta(2) 3.4 at 298.2 K. Absorption spectra of the complexes were calculated and analysed by deconvolution technique. Derivative spectrophotometry for the chemical model determination has also been successfully applied.     

Toward optimized high-relaxivity MRI agents: thermodynamic selectivity of hydroxypyridonate/catecholate ligands

The thermodynamic selectivity for Gd(3+) relative to Ca(2+), Zn(2+), and Fe(3+) of two ligands of potential interest as magnetic resonance imaging (MRI) contrast agents has been determined by NMR spectroscopy and potentiometric and spectrophotometric titration. The two hexadentate ligands TREN-6-Me-3,2-HOPO (H(3)L2) and TREN-bisHOPO-TAM-EA (H(4)L3) incorporate 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties. They were chosen to span a range of basicity while maintaining a structural motif similar to that of the parent ligand, TREN-1-Me-3,2-HOPO (H(3)L1), in order to investigate the effect of the ligand basicity on its selectivity. The 1:1 stability constants (beta(110)) at 25 degrees C and 0.1 M KCl are as follows. L2: Gd(3+), 20.3; Ca(2+), 7.4; Zn(2+), 11.9; Fe(3+), 27.9. L3: Gd(3+), 24.3; Ca(2+), 5.2; Zn(2+), 14.6; Fe(3+), 35.1. At physiological pH, the selectivity of the ligand for Gd(3+) over Ca(2+) increases with the basicity of the ligand and decreases for Gd(3+) over Fe(3+). These trends are consistent with the relative acidities of the various metal ions;- more basic ligands favor harder metals with a higher charge-to-radius ratio. The stabilities of the Zn(2+) complexes do not correlate with basicity and are thought to be more influenced by geometric factors. The selectivities of these ligands are superior to those of the octadentate poly(aminocarboxylate) ligands that are currently used as MRI contrast agents in diagnostic medicine.     

The influence of linker geometry in bis(3-hydroxy-N-methyl-pyridin-2-one) ligands on solution phase uranyl affinity

Seven water-soluble, tetradentate bis(3-hydroxy-N-methyl-pyridin-2-one) (bis-Me-3,2-HOPO) ligands were synthesized that vary only in linker geometry and rigidity. Solution-phase thermodynamic measurements were conducted between pH 1.6 and pH 9.0 to determine the effects of these variations on proton and uranyl cation affinity. Proton affinity decreases by introduction of the solubilizing triethylene glycol group as compared to unsubstituted reference ligands. Uranyl affinity was found to follow no discernable trends with incremental geometric modification. The butyl-linked 4 li-Me-3,2-HOPO ligand exhibited the highest uranyl affinity, consistent with prior in vivo decorporation results. Of the rigidly-linked ligands, the o-phenylene linker imparted the best uranyl affinity to the bis-Me-3,2-HOPO ligand platform.     

1,2-hydroxypyridonates as contrast agents for magnetic resonance imaging: TREN-1,2-HOPO

1,2-Hydroxypyridinones (1,2-HOPO) form very stable lanthanide complexes that may be useful as contrast agents for magnetic resonance imaging (MRI). X-ray diffraction of single crystals established that the solid-state structures of the Eu(III) and the previously reported [Inorg. Chem. 2004, 43, 5452] Gd(III) complex are identical. The recently discovered sensitizing properties of 1,2-HOPO chelates for Eu(III) luminescence [J. Am. Chem. Soc. 2006, 128, 10 067] allow for direct measurement of the number of water molecules coordinated to the metal center. Fluorescence measurements of the Eu(III) complex corroborate that, in solution, two water molecules coordinate the lanthanide (q = 2) as proposed from the analysis of NMRD profiles. In addition, fluorescence measurements have verified the anion binding interactions of lanthanide TREN-1,2-HOPO complexes in solution, studied by relaxivity, revealing only very weak oxalate binding (KA = 82.7 +/- 6.5 M-1). Solution thermodynamic studies of the metal complex and free ligand have been carried out using potentiometry, spectrophotometry, and fluorescence spectroscopy. The metal ion selectivity of TREN-1,2-HOPO supports the feasibility of using 1,2-HOPO ligands for selective lanthanide binding [pGd = 19.3 (2), pZn = 15.2 (2), pCa = 8.8 (3)].     

Synthesis, solution behavior, thermal stability, and biological activity of an Fe(III) complex of an artificial siderophore with intramolecular hydrogen bonding networks

Previously, an artificial siderophore complex, the iron(III) complex with tris[2-[(N-acetyl-N-hydroxy)glycylamino]ethyl]amine (TAGE), was constructed in order to understand the effect of intramolecular hydrogen bonding interaction on the siderophore function, and its structural characterization in the solid state was reported (Inorg. Chem. 2001, 40, 190). In this paper, the solution behavior of the M(III)-TAGE (M = Fe, Ga) system has been investigated using (1)H NMR, UV-vis, and FAB mass spectroscopies in efforts to characterize the biological implication of hydrogen bonding networks between the amide hydrogens and coordinating aminohydroxy oxygens of the complex. The temperature dependence of (1)H NMR spectra for Ga(III) complex of TAGE indicates that hydrogen bonding networks are maintained in polar solvents such as DMSO-d(6) and D(2)O. The UV-vis spectra of the Fe(III)-TAGE system under various pH conditions have shown that TAGE forms a tris(hydroxamato)iron(III) complex in an aqueous solution in the pH range 4-8. By contrast, tris[2-[(N-acetyl-N-hydroxy)propylamido]ethyl]amine (TAPE; TAGE analogue that is difficult to form intramolecular hydrogen bonding networks), which has been synthesized as a comparison of TAGE, forms both of bis- and tris(hydroxamato)iron(III) complexes in the same pH range. Both the stability constants (log beta(FeTAGE) = 28.6; beta(FeTAGE) = [Fe(III)TAGE]/([Fe(3+)][TAGE(3)(-)])) and pM (-log[Fe(3+)]) value for Fe(III)TAGE (pM 25) are comparable to those of a natural siderophore ferrichrome (log beta = 29.1 and pM 25.2). The kinetic study of the TAGE-Fe(III) system has given the following rate constants: the rate of the ligand exchange reaction between Fe(III)TAGE and EDTA is 6.7 x 10(-4) s(-1), and the removal rates of iron from diferric bovine plasma transferrin by TAGE are 2.8 x 10(-2) and 6.0 x 10(-3) min(-1). These values are also comparable to those of a natural siderophore desferrioxamine B under the same conditions. In a biological activity experiment, TAGE has promoted the growth of the siderophore-auxotroph Gram-positive bacterium Microbacterium flavescens, suggesting that TAGE mimics the activity of ferrichrome. These results indicate that the artificial siderophore with intramolecular hydrogen bonding networks, TAGE, is a good structural and functional model for a natural ferrichrome.     

Sequestering ability of polycarboxylic ligands towards dioxouranium(VI)

In this paper we report a comparison on the sequestering ability of some polycarboxylic ligands towards dioxouranium(VI) (UO(2)(2+), uranyl). Ligands taken into account are mono- (acetate), di- (oxalate, malonate, succinate and azelate), tri- (1,2,3-propanetricarboxylate) and hexa-carboxylate (1,2,3,4,5,6-benzenehexacarboxylate). The sequestering ability of polycarboxylic ligands towards UO(2)(2+) was quantified by a new approach expressed by means of a sigmoid Boltzman type equation and of a empirical parameters (pL(50)) which defines the amount of ligand necessary to sequester 50% of the total UO(2)(2+) concentration. A fairly linear correlation was obtained between pL(50) or log K(110) (log K(110) refers to the equilibrium: UO(2)(2+)+L(z-)=UO(2)L((2-z)); L=generic ligand) and the polyanion charges. In order to complete the picture, a tetra-carboxylate ligand (1,2,3,4-butanetetracarboxylate) was studied in NaCl aqueous solutions at 0相似文献   

Conjugation effects of various linkers on Gd(III) MRI contrast agents with dendrimers: optimizing the hydroxypyridinonate (HOPO) ligands with nontoxic, degradable esteramide (EA) dendrimers for high relaxivity

One essential requirement for more sensitive gadolinium-based MRI contrast agents is to slow the molecular tumbling of the gadolinium(III) ion, which increases the gadolinium's relaxivity (i.e., its ability to speed up the NMR relaxation of nearby water molecules). One route to this is through conjugation to high-molecular-weight polymers such as dendrimers. In this work, amine-functionalized TREN-bis(1,2-HOPO)-TAM-ethylamine and TREN-bis(1-Me-3,2-HOPO)-TAM-ethylamine ligands have been synthesized and attached to biocompatible 40 kDa esteramide (EA)- and poly-l-lysine (PLL)-based dendrimers capable of binding up to eight gadolinium complexes. These conjugates have T(1) relaxivities of up to 38.14 ± 0.02 mM(-1) s(-1) per gadolinium at 37 °C, corresponding to relaxivities of up to 228 mM(-1) s(-1) per dendrimer molecule. This relaxivity expressed on a "per Gd" basis is several times that of the small-molecule complexes and an order of magnitude higher than that of current commercial agents. Because of their high performance and low toxicity, these macromolecules may constitute an attractive complement to currently available gadolinium(III)-based contrast agents.     

EDTA and mixed-ligand complexes of tetravalent and trivalent plutonium

EDTA forms stable complexes with plutonium that are integral to nuclear material processing, radionuclide decontamination, and the potentially enhanced transport of environmental contamination. To characterize the aqueous Pu(4+/3+)EDTA species formed under the wide range of conditions of these processes, potentiometry, spectrophotometry, and cyclic voltammetry were used to measure solution equilibria. The results reveal new EDTA and mixed-ligand complexes and provide more accurate stability constants for previously identified species. In acidic solution (pH < 4) and at 1:1 ligand to metal ratio, PuY (where Y4- is the tetra-anion of EDTA) is the predominant species, with an overall formation constant of log beta110 = 26.44. At higher pH, the hydrolysis species, PuY(OH)- and PuY(OH)(2)2-, form with the corresponding overall stability constants log beta(11 - 1) = 21.95 and log beta(11 - 2) = 15.29. The redox potential of the complex PuY at pH = 2.3 was determined to be E(1/2) = 342 mV. The correlation between redox potential, pH, and the protonation state of PuY- was derived to estimate the redox potential of the Pu(4+/3+)Y complex as a function of pH. Under conditions of neutral pH and excess EDTA relative to Pu4+, PuY(2)4- forms with an overall formation constant of log beta120 = 35.39. In the presence of ancillary ligands, mixed-ligand complexes form, as exemplified by the citrate and carbonate complexes PuY(citrate)3- (log beta1101 = 33.45) and PuY(carbonate)2- (log beta1101 = 35.51). Cyclic voltammetry shows irreversible electrochemical behavior for these coordinatively saturated Pu4+ complexes: The reduction wave is shifted approximately -400 mV from the reduction wave of the complex PuY, while the oxidation wave is invariant.     

Novel pyrano[3,2-b]indole derivatives: synthesis and some properties

Acid treatment of β-(3-acetoxyindol-2-yl)-α-cyanoacrylic acid derivatives (ethyl ester and nitrile) with aqueous or gaseous HCl afforded novel 3-substituted 2-oxo-2,5-dihydropyra-no[3,2-b]indoles. 2-Oxo-2,5-dihydropyrano[3,2-b]indole-3-carbonitrile was converted into ethyl 2-oxo-2,5-dihydropyrano[3,2-b]indole-3-carboximidate.     

A bidentate terephthalamide ligand, TAMmeg, as an entry into terephthalamide-containing therapeutic iron chelating agents

A new bidentate 2,3-dihydroxyterephthalamide ligand, 2,3-dihydroxy-N,N'-bis(2-methoxyethyl)terephthalamide (TAMmeg), has been prepared. The ligand, its synthetic precursor 2,3-bis(benzyloxy)-N,N'-bis(2-methoxy-ethyl)-terephthalamide (BnTAMmeg), and its iron complex have been structurally characterized by X-ray diffraction. BnTAMmeg crystallizes in the monoclinic space group P2(1)/n with cell parameters a = 14.4976(14) A, b = 11.5569(11) A, c = 16.3905(16) A, beta = 113.621(1) degrees , and Z = 4. TAMmeg crystallizes in the monoclinic space group P2(1)/c with cell parameters a = 13.8060(36) A, b = 8.0049(21) A, c = 19.4346(50) A, beta = 106.855(4) degrees , and Z = 4. Fe[TAMmeg] crystallizes in the triclinic space group P with cell parameters a = 12.9565(14) A, b = 13.4514(14) A, c = 20.2092(21) A, alpha = 102.093(2) degrees , beta = 95.433(2) degrees , gamma = 101.532(2) degrees , and Z = 2. The aqueous protonation and ferric ion coordination chemistry of TAMmeg were examined using potentiometric and spectrophotometric methods. Proton association constants and iron complex formation constants for the ligand are as follows: log beta(011) = 10.32, log beta(012) = 16.49, log beta(110) = 17.9, log beta(120) = 32.1, and log beta(130) = 43.0. The ferric complex of TAMmeg is surprisingly stable for a bidentate terephthalamide iron complex. The only more-stable bidentate terephthalamide iron complex that has been reported contains a ligand with positively charged pendant arms.     

Condensation reactions of 3-oxo-2-arylhydrazonopropanals with active methylene reagents: formation of 2-hydroxy- and 2-amino-6-substituted-5-arylazonicotinates and pyrido[3,2-c]cinnolines via 6π-electrocyclization reactions

3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-ptolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2–c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a-c to yield pyridazinones 13a-c.