H-HoPro-OH

Solution thermodynamic stability of complexes formed with the octadentate hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO): a critical feature for efficient chelation of lanthanide(IV) and actinide(IV) ions

The solution thermodynamics of water-soluble complexes formed between Ce(III), Ce(IV), Th(IV) and the octadentate chelating agent 3,4,3-LI(1,2-HOPO) were investigated. Several techniques including spectrofluorimetric and automated spectrophotometric titrations were used to overcome the slow spontaneous oxidation of Ce(III) complexes yielding to stability constants of log β110 = 17.4 ± 0.5, log β11-1 = 8.3 ± 0.4 and log β111 = 21.2 ± 0.4 for [Ce(III)(3,4,3-LI(1,2-HOPO))](-), [Ce(III)(3,4,3-LI(1,2-HOPO)(OH)](2-), and [Ce(III)(3,4,3-LI(1,2-HOPO)H], respectively. Using the spectral properties of the hydroxypyridinonate chelator in ligand competition titrations against nitrilotriacetic acid, the stability constant log β110 = 41.5 ± 0.5 was determined for [Ce(IV)(3,4,3-LI(1,2-HOPO))]. Finally, the extraordinarily stable complex [Ce(IV)(3,4,3-LI(1,2-HOPO))] was used in Th(IV) competition titrations, resulting in a stability constant of log β110 = 40.1 ± 0.5 for [Th(IV)3,4,3-LI(1,2-HOPO))]. These experimental values are in excellent agreement with previous estimates, they are discussed with respect to the ionic radius and oxidation state of each cationic metal, and allow predictions on the stability of other actinide complexes including [U(IV)(3,4,3-LI(1,2-HOPO))], [Np(IV)(3,4,3-LI(1,2-HOPO))], and [Pu(IV)(3,4,3-LI(1,2-HOPO))]. Comparisons with the standard ligand diethylenetriamine pentaacetic acid (DTPA) provide a thermodynamic basis for the observed significantly higher efficacy of 3,4,3-LI(1,2-HOPO) as an in vivo actinide decorporation agent.

Chromium complexes bearing disubstituted organophosphate ligands and their use in ethylene polymerization

The crystal structures of three unusual chromium organophosphate complexes have been determined, namely, bis(μ-butyl 2,6-di-tert-butyl-4-methylphenyl hydrogen phosphato-κO:κO')di-μ-hydroxido-bis[(butyl 2,6-di-tert-butyl-4-methylphenyl hydrogen phosphato-κO)(butyl 2,6-di-tert-butyl-4-methylphenyl phosphato-κO)chromium](Cr-Cr) heptane disolvate or {Cr₂(μ₂-OH)₂[μ₂-PO₂(OBu)(O-2,6-^tBu₂-4-MeC₆H₂)-κO:κO']₂[PO₂(OBu)(O-2,6-^tBu₂-4-MeC₆H₂)-κO]₂[HOPO(OBu)(O-2,6-^tBu₂-4-MeC₆H₂)-κO]₂}·2C₇H₁₆, [Cr₂(C₁₉H₃₂O₄P)₄(C₁₉H₃₃O₄P)₂(OH)₂]·2C₇H₁₆, denoted (1)·2(heptane), [μ-bis(2,6-diisopropylphenyl) phosphato-1κO:2κO']bis[bis(2,6-diisopropylphenyl) phosphato]-1κO,2κO-chlorido-2κCl-triethanol-1κ²O,2κO-di-μ-ethanolato-1κ²O:2κ²O-dichromium(Cr-Cr) ethanol monosolvate or {Cr₂(μ₂-OEt)₂[μ₂-PO₂(O-2,6-ⁱPr₂-C₆H₃)₂-κO:κO'][PO₂(O-2,6-ⁱPr₂-C₆H₃)₂-κO]₂Cl(EtOH)₃}·EtOH, [Cr₂(C₂H₅O)₂(C₂₄H₃₄O₄P)₃Cl(C₂H₆O)₃]·C₂H₆O, denoted (2)·EtOH, and di-μ-ethanolato-1κ²O:2κ²O-bis{[bis(2,6-diisopropylphenyl) hydrogen phosphato-κO][bis(2,6-diisopropylphenyl) phosphato-κO]chlorido(ethanol-κO)chromium}(Cr-Cr) benzene disolvate or {Cr₂(μ₂-OEt)₂[PO₂(O-2,6-ⁱPr₂-C₆H₃)₂-κO]₂[HOPO(O-2,6-ⁱPr₂-C₆H₃)₂-κO]₂Cl₂(EtOH)₂}·2C₆H₆, [Cr₂(C₂H₅O)₂(C₂₄H₃₄O₄P)₂(C₂₄H₃₅O₄P)₂Cl₂(C₂H₆O)₂]·2C₆H₆, denoted (3)·2C₆H₆. Complexes (1)-(3) have been synthesized by an exchange reaction between the in-situ-generated corresponding lithium or potassium disubstituted phosphates with CrCl₃(H₂O)₆ in ethanol. The subsequent crystallization of (1) from heptane, (2) from ethanol and (3) from an ethanol/benzene mixture allowed us to obtain crystals of (1)·2(heptane), (2)·EtOH and (3)·2C₆H₆, whose structures have the monoclinic P2₁, orthorhombic P2₁2₁2₁ and triclinic P-1 space groups, respectively. All three complexes have binuclear cores with a single Cr-Cr bond, i.e. Cr₂O₆P₂ in (1), Cr₂PO₄ in (2) and Cr₂O₂ in (3), where the Cr atoms are in distorted octahedral environments, formally having 16 ē per Cr atom. The complexes have bridging ligands μ₂-OH in (1) or μ₂-OEt in (2) and (3). The organophosphate ligands demonstrate terminal κO coordination modes in (1)-(3) and bridging μ₂-κO:κO' coordination modes in (1) and (2). All the complexes exhibit hydrogen bonding: two intramolecular O_phos...H-O_phos interactions in (1) and (3) form two {H[PO₂(OR)₂]₂} associates; two intramolecular Cl...H-O_Et hydrogen bonds additionally stabilize the Cr₂O₂ core in (3); two intramolecular O_phos...H-O_Et interactions and two O...H-O intermolecular hydrogen bonds with a noncoordinating ethanol molecule are observed in (2)·EtOH. The presence of both basic ligands (OH^- or OEt^-) and acidic [H(phosphate)₂]^- associates at the same metal centres in (1) and (3) is rather unusual. Complexes may serve as precatalysts for ethylene polymerization under mild conditions, providing polyethylene with a small amount of short-chain branching. The formation of a small amount of α-olefins has been detected in this reaction.

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.

Preparation and characterization of inorganic radioactive holmium-166 microspheres for internal radionuclide therapy

Microspheres with high specific activities of radionuclides are very interesting for internal radiotherapy treatments. This work focuses on the formulation and characterization of inorganic microspheres with a high content of holmium and therefore a high specific radioactivity of holmium-166. Two novel formulations of inorganic microspheres were obtained by dispersing solid holmium acetylacetonate microspheres (Ho₂(AcAc)₃-ms) in NaH₂PO₄ or NaOH solutions followed by 2 h incubation at room temperature. By exchange of acetylacetonate with phosphate or hydroxyl ions, holmium phosphate microspheres (HoPO₄-ms) and holmium hydroxide microspheres (Ho(OH)₃-ms) were formed respectively. The inorganic microspheres had a significantly smaller diameter (28.5 ± 4.4 μm (HoPO₄-ms) and 25.1 ± 3.5 μm (Ho(OH)₃-ms)) than those of Ho₂(AcAc)₃-ms (32.6 ± 5.2 μm). The weight percentage of holmium-165 in the microspheres increased significantly from 47% (Ho₂(AcAc)₃-ms) to 55% (HoPO₄-ms) and 73% (Ho(OH)₃-ms). After preparation of both HoPO₄-ms and Ho(OH)₃-ms, the stable holmium-165 isotope was partly converted by neutron activation into radioactive holmium-166 to yield radioactive microspheres. High specific activities were achieved ranging from 21.7 to 59.9 MBq/mg (¹⁶⁶HoPO₄-ms) and from 28.8 to 79.9 MBq/mg (¹⁶⁶Ho(OH)₃-ms) depending on the neutron activation time. The structure of both microspheres was preserved up to neutron activations of 6 h in a thermal neutron flux of 4.72 × 10¹⁶ n m^-2 s^-1. After activation, both microspheres revealed excellent stability in administration fluids (saline and phosphate buffer) having less than 0.05% of holmium released after 72 h incubation. Finally, the hemocompatibility of these inorganic microspheres was evaluated and it was shown that the microspheres did cause neither hemolysis nor depletion or inhibition of the coagulation factors of the intrinsic blood coagulation pathway meaning that the microspheres have a good hemocompatibility. Overall, this work shows that radioactive inorganic microspheres with high specific activities of holmium-166 can be prepared which potentially can be used for internal radionuclide therapy.

Protocol for efficient solid-phase synthesis of peptides containing 1-hydroxypyridine-2-one (1,2-HOPO)

?Metal chelation has found many applications that directly affect human's life.?Natural siderophores are one of the most potent chelators for Fe (III)?1-Hydroxypyridine-2-one (1,2-HOPO) (Fig. 1a), which is shown in 4-carboxy-1-hydroxypyridin-2-one (1,2-HOPO-4-COOH) (Fig. 1b), is a moiety that electronically resembles the hydroxamate group found in natural siderophores (Fig. 1c). Of note, 1,2-HOPO moiety is present in the natural siderophore cepabactin [1]?Synthesis of 1,2-HOPO containing chelators has been carried in solid phase using carboxylic acid derivatives of 1,2-HOPO and required the protection of the reactive hydroxyl group usually with benzyl group (Bzl). After the peptide elongation, the Bzl group has been removed on the same solid phase using a bit harsh conditions: 0.1 M BBr₃ in DCM for 60 min [2], 10% HBr in AcOH for 14 h [3]; in solution: 1 M BCl₃ in DCM for 2 d [4], 50% HCl in AcOH for 4 d [5], H2-Pd/C, AcOH-MeOH [6].?First of all, a method for the incorporation of the 1,2-HOPO-4-COOH through its carboxyl group into the peptide backbone without protecting the N-OH is proposed (the presence of the carboxyl group facilitates the attachment).?Furthermore, in the cases that Bzl protection is required for the N-OH, a friendlier method for removing the Bzl is described. The removal of the Bzl is done concomitantly to the global deprotection and cleavage of the peptide from the resin using TFA- TFMSA-H₂O (8:3:1).