An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol

An improved synthesis of (2E,4Z)-6-(benzyloxy)-4-bromohexa-2,4-dien-1-ol has been devised. This new route increases the throughput and yield of the diene product by circumventing a low yielding preparation of boronic acid intermediate as well as removing the need to use multi-gram quantities of highly toxic thallium salts. In the process of developing this new route, a higher yielding preparation of ( E)-3-hydroxyprop-1-enylboronic acid was also achieved. (c) 2007 Elsevier Ltd. All rights reserved

High relaxivity Mn2+-based MRI contrast agents

[Abstract] Stable Mn2+ mono- and binuclear complexes containing pentadentate 6,6′-((methylazanediyl)bis(methylene)) dipicolinic acid coordinating units give remarkably high relaxivities due to the presence of two inner-sphere water molecules. The mononuclear derivative binds human serum albumin (HSA) with an association constant of 3372 M−1, which results in the replacement of the coordinated water molecules by donor atoms of protein residues. The dinuclear analogue also binds HSA while leaving one of the Mn2+ centres exposed to the solvent with two coordinated water molecules. Thus, this complex shows remarkably high relaxivities upon protein binding (39.0 mM−1 s−1 per Mn, at 20 MHz and 37 °C).Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; EM 2012/088Galicia. Consellería de Cultura, Educación e Ordenación Universitaria; CN 2012/01

Self‐aggregated dinuclear lanthanide(III) complexes as potential bimodal probes for magnetic resonance and optical imaging

[Abstract] Homodinuclear lanthanide complexes (Ln=La, Eu, Gd, Tb, Yb and Lu) derived from a bis‐macrocyclic ligand featuring two 2,2′,2′′‐(1,4,7,10‐tetraazacyclododecane‐1,4,7 triyl)triacetic acid chelating sites linked by a 2,6‐bis(pyrazol‐1‐yl)pyridine spacer (H2L3) were prepared and characterized. Luminescence lifetime measurements recorded on solutions of the EuIII and TbIII complexes indicate the presence of one inner‐sphere water molecule coordinated to each metal ion in these complexes. The overall luminescence quantum yields were determined (∅H2O=0.01 for [Eu2(L3)] and 0.50 for [Tb2(L3)] in 0.01 MTRIS/HCl, pH 7.4; TRIS=tris(hydroxymethyl)aminomethane), pointing to an effective sensitization of the metal ion by the bispyrazolylpyridyl unit of the ligand, especially with Tb. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd2(L3)] are characteristic of slowly tumbling systems, showing a low‐field plateau and a broad maximum around 30 MHz. This suggests the occurrence of aggregation of the complexes giving rise to slowly rotating species. A similar behavior is observed for the analogous GdIII complex containing a 4,4′ dimethyl‐2,2′‐bipyridyl spacer ([Gd2(L1)]). The relaxivity of [Gd2(L3)] recorded at 0.5 T and 298 K (pH 6.9) amounts to 13.7 mM−1 s−1. The formation of aggregates has been confirmed by dynamic light scattering (DLS) experiments, which provided mean particle sizes of 114 and 38 nm for [Gd2(L1)] and [Gd2(L3)], respectively. TEM images of [Gd2(L3)] indicate the formation of nearly spherical nanosized aggregates with a mean diameter of about 41 nm, together with some nonspherical particles with larger size.Ministerio de Educación y Ciencia; CTQ2009‐10721Xunta de Galicia; IN845B‐2010/06

M tuberculosis in the adjuvant modulates time of appearance of CNS-specific effector T cells in the spleen through a polymorphic site of TLR2

DC deliver information regulating trafficking of effector T cells along T-cell priming. However, the role of pathogen-derived motives in the regulation of movement of T cells has not been studied. We hereinafter report that amount of M tuberculosis in the adjuvant modulates relocation of PLP139-151 specific T cells. In the presence of a low dose of M tuberculosis in the adjuvant, T cells (detected by CDR3 BV-BJ spectratyping, the so-called "immunoscope") mostly reach the spleen by day 28 after immunization ("late relocation") in the SJL strain, whereas T cells reach the spleen by d 14 with a high dose of M tuberculosis ("early relocation"). The C57Bl/6 background confers a dominant "early relocation" phenotype to F1 (SJL 7C57Bl/6) mice, allowing early relocation of T cells in the presence of low dose M tuberculosis. A single non-synonymous polymorphism of TLR2 is responsible for "early/late" relocation phenotype. Egress of T lymphocytes is regulated by TLR2 expressed on T cells. Thus, pathogens engaging TLR2 on T cells regulate directly T-cell trafficking, and polymorphisms of TLR2 condition T-cell trafficking upon a limiting concentration of ligand

H-1 and O-17 NMR Relaxometric and Computational Study on Macrocyclic Mn(II) Complexes

Herein we report a detailed H-1 and O-17 relaxometric investigation of Mn(II) complexes with cyclenbased ligands such as 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (DO IA), 2,2 '-(1,4,7,10-tetraazacyclododecane-1,4-diyI)diacetic acid (1,4-DO2A), 2,2 '-(1,4,7,10-tetraazacyclododecane1,7-diyOdiacetic acid (1,7-DO2A), and 2,2 ',2 ''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyOtriacetic acid (DO3A). The Mn(II) complex with the heptadentate ligand DO3A does not have inner sphere water molecules (q = 0), and therefore, the metal ion is most likely seven-coordinate. The hexadentate DO2A ligand has two isomeric forms: 1,7-DO2A and 1,4-DO2A. The Mn(II) complex with 1,7-DO2A is predominantly six-coordinate (q= 0). In aqueous solutions of [Mn(1,4-DO2A)], a species with one coordinated water molecule (q = 1) prevails largely, whereas a q = 0 form represents only about 10% of the overall population. The Mn(II) complex of the pentadentate ligand DOIA also contains a coordinated water molecule. DFT calculations (B3LYP model) are used to obtain information about the structure of this family of closely related complexes in solution, as well as to determine theoretically the '70 and 1H hyperfine coupling constants responsible for the scalar contribution to O-17 and H-1 NMR relaxation rates and 170 NMR chemical shifts. These calculations provide O-17 A/h values of ca. 40 x 10(6) rad s(-1), in good agreement with experimental data. The [Mn(1,4-DO(2)A)(H2O)] complex is endowed with a relatively fast water exchange rate (Icex2 '' = 11.3 X 108 s-1) in comparison to the [Mn(EDTA)(H20)}2analogue (kr = 4.7 X 108 s-1), but about 5 times lower than that of the [Mn(D01A)(H20))* complex (1c,x2 ''= 60 X 108 s-1). The water exchange rate measured for the latter complex represents the highest water exchange rate ever measured for a Mn(II) complex

¹H and ¹⁷O NMR Relaxometric and Computational Study on Macrocyclic Mn(II) Complexes

Herein we report a detailed ¹H and ¹⁷O relaxometric investigation of Mn­(II) complexes with cyclen-based ligands such as 2-(1,4,7,10-tetraazacyclododecan-1-yl)­acetic acid (DO1A), 2,2′-(1,4,7,10-tetraazacyclododecane-1,4-diyl)­diacetic acid (1,4-DO2A), 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl)­diacetic acid (1,7-DO2A), and 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)­triacetic acid (DO3A). The Mn­(II) complex with the heptadentate ligand DO3A does not have inner sphere water molecules (<i>q</i> = 0), and therefore, the metal ion is most likely seven-coordinate. The hexadentate DO2A ligand has two isomeric forms: 1,7-DO2A and 1,4-DO2A. The Mn­(II) complex with 1,7-DO2A is predominantly six-coordinate (<i>q</i> = 0). In aqueous solutions of [Mn­(1,4-DO2A)], a species with one coordinated water molecule (<i>q</i> = 1) prevails largely, whereas a <i>q</i> = 0 form represents only about 10% of the overall population. The Mn­(II) complex of the pentadentate ligand DO1A also contains a coordinated water molecule. DFT calculations (B3LYP model) are used to obtain information about the structure of this family of closely related complexes in solution, as well as to determine theoretically the ¹⁷O and ¹H hyperfine coupling constants responsible for the scalar contribution to ¹⁷O and ¹H NMR relaxation rates and ¹⁷O NMR chemical shifts. These calculations provide ¹⁷O <i>A</i>/ℏ values of ca. 40 × 10⁶ rad s^–1, in good agreement with experimental data. The [Mn­(1,4-DO2A)­(H₂O)] complex is endowed with a relatively fast water exchange rate (<i>k</i>_ex²⁹⁸ = 11.3 × 10⁸ s^–1) in comparison to the [Mn­(EDTA)­(H₂O)]^2‑ analogue (<i>k</i>_ex²⁹⁸ = 4.7 × 10⁸ s^–1), but about 5 times lower than that of the [Mn­(DO1A)­(H₂O)]⁺ complex (<i>k</i>_ex²⁹⁸ = 60 × 10⁸ s^–1). The water exchange rate measured for the latter complex represents the highest water exchange rate ever measured for a Mn­(II) complex

Picolinate-Containing Macrocyclic Mn(II) Complexes as Potential MRI Contrast Agents

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Hyperfine Coupling Constants on Inner-Sphere Water Molecules of a Triazacyclononane-based Mn(II) Complex and Related Systems Relevant as MRI Contrast Agents

We report the synthesis of the ligand H₂MeNO2A (1,4-bis­(carboxymethyl)-7-methyl-1,4,7-triazacyclononane) and a detailed experimental and computational study of the hyperfine coupling constants (HFCCs) on the inner-sphere water molecules of [Mn­(MeNO2A)] and related Mn²⁺ complexes relevant as potential contrast agents in magnetic resonance imaging (MRI). Nuclear magnetic relaxation dispersion (NMRD) profiles, ¹⁷O NMR chemical shifts, and transverse relaxation rates of aqueous solutions of [Mn­(MeNO2A)] were recorded to determine the parameters governing the relaxivity in this complex and the ¹⁷O and ¹H HFCCs. DFT calculations (TPSSh model) performed in aqueous solution (PCM model) on the [Mn­(MeNO2A)­(H₂O)]·<i>x</i>H₂O and [Mn­(EDTA)­(H₂O)]^2–·<i>x</i>H₂O (<i>x</i> = 0–4) systems were used to determine theoretically the ¹⁷O and ¹H HFCCs responsible for the ¹⁷O NMR chemical shifts and the scalar contributions to ¹⁷O and ¹H NMR relaxation rates. The use of a mixed cluster/continuum approach with the explicit inclusion of a few second-sphere water molecules is critical for an accurate calculation of HFCCs of coordinated water molecules. The impact of complex dynamics on the calculated HFCCs was evaluated with the use of molecular dynamics simulations within the atom-centered density matrix propagation (ADMP) approach. The ¹⁷O and ¹H HFCCs calculated for these complexes and related systems show an excellent agreement with the experimental data. Both the ¹H and ¹⁷O HFCCs (<i>A</i>_iso values) are dominated by the spin delocalization mechanism. The <i>A</i>_iso values are significantly affected by the distance between the oxygen atom of the coordinated water molecule and the Mn²⁺ ion, as well as by the orientation of the water molecule plane with respect to the Mn–O vector

Picolinate-Containing Macrocyclic Mn²⁺ Complexes as Potential MRI Contrast Agents

We report the synthesis of the ligand Hnompa (6-((1,4,7-triaza­cyclononan-1-yl)­methyl)­picolinic acid) and a detailed characterization of the Mn²⁺ complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetra­azacyclo­dodecan-1-yl)­methyl)­picolinic acid) and Htempa (6-((1,4,8,11-tetra­azacyclo­tetradecan-1-yl)­methyl)­picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of log<i>K</i>_MnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn²⁺ complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn₂(nompa)₂(H₂O)₂]­(ClO₄)₂ shows that the Mn²⁺ ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa^– ligand acting as a bridging bidentate carboxylate group (μ–η¹-carboxylate). Nuclear magnetic relaxation dispersion (¹H NMRD) profiles and ¹⁷O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn­(nompa)]⁺ indicate that the Mn²⁺ ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the ¹H NMRD and ¹⁷O NMR data provides a very high water exchange rate of the inner-sphere water molecule (<i>k</i>_ex²⁹⁸ = 2.8 × 10⁹ s^–1) and an unusually high value of the ¹⁷O hyperfine coupling constant of the coordinated water molecule (<i>A</i>_O/ℏ = 73.3 ± 0.6 rad s^–1). DFT calculations performed on the [Mn­(nompa)­(H₂O)]⁺·2H₂O system (TPSSh model) provide a <i>A</i>_O/ℏ value in excellent agreement with the one obtained experimentally