- Tri- and tetranuclear RuII-Gd III 2 and RuII-Gd III 3 d-f heterometallic complexes as potential bimodal imaging probes for MRI and optical imaging
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The synthesis of tri- and tetranuclear RuII-GdIII2 and RuII-GdIII3 d-f heterometallic complexes of 4-aminopyridine-appended DO3A (DOTA-AMpy, 4) with 1,10-phenanthroline and 4′-(p-tolyl)-2,2′:6′,2′′-terpyridine ancillary ligands and their relaxometry and in vitro cytotoxicity studies are reported. Complexes [Ru(phen)2{Gd(DOTA-AMpy)(H2O)}2]Cl2 (7) and [Ru(ttpy){Gd(DOTA-AMpy)(H2O)}3]Cl2 (9) exhibit the "per Gd" longitudinal relaxivity of 6.19 and 7.47 mM-1 s-1 and 15.37 and 18.61 mM-1 s-1, respectively, in aqueous solution and in the presence of HSA (20 MHz, pH = 7.4, phosphate buffer saline, 37 °C). Complex 7 exhibits an emission band at 590 nm. The cell viability and cytotoxicity studies of complexes 7 and 9 against the HeLa cell lines by MTT assay demonstrate their cytotoxic activity with the IC50 values of 52.1 and 27.9 μM, respectively. Morphological assessment of apoptosis by acridine orange and ethidium bromide staining and by Hoechst-33342 assay shows marked morphological signs of apoptosis in a dose-dependent manner. Flow cytometric analysis by propidium iodide staining indicates the inhibition of HeLa cell proliferation and DNA ladder assay shows apoptotic cell death, lending support to the antitumor activity of 7 and 9. A molecular docking study reveals that these complexes intercalate with DNA and bind to HSA. Relaxometry and cytotoxicity studies indicate that complexes 7 and 9 could be used as potential bimodal imaging probes and as anticancer agents.
- Nithyakumar,Alexander
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- Synthesis and relaxivity studies of a gadolinium(III) complex of ATP-conjugated DO3A as a contrast enhancing agent for MRI
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A gadolinium(III) complex of adenosine 5′-triphosphate (ATP)-appended DO3A has been synthesized in order to attain higher relaxivity and to reduce the in vivo toxicity. DO3A (2) was synthesized as the exclusive product by a single step direct trialkylation of cyclen with chloroacetic acid in water (pH 10, -4°C). ATP was then covalently appended to the DO3A framework through a propyl linker. The 3-bromopropane spacer appended DO3A (3) was synthesized by the reaction of DO3A with 1,3-dibromopropane in water/DMF in the presence of triethylamine as proton scavenger. The ATP-appended DO3A (DOSA-Pr-ATP) was synthesized by the reaction of 3 with ATP in water at room temperature. [Gd(DOSA-Pr-ATP)(H2O)2] (4) was synthesized by the reaction of DOSA-Pr-ATP with gadolinium(III) perchlorate hydrate in water. The X- and Q-band EPR spectra of 4 contain a broad band with no hyperfine splitting at both room temperature and liquid nitrogen temperature. The g-values are 2.167 and 2.033 at X- and Q-band, respectively. The magnetic moment of 4 is 7.45 BM which is close to the value for free GdIII ion. The longitudinal relaxivity, r1p, of [Gd(DO3A-Pr-ATP)(H2O)2] is 6.51 mM-1s-1 (24 MHz and 35±0.1°C), which is higher than that of [Gd(DOTA)(H2O)]- (r1p = 3.50 mM-1s-1, 20 MHz, 39°C, pH 7.3) and [Gd(DO3A)-(H2O)2] (r1p = 4.8 mM -1s-1, 20 MHz, 40°C). The higher relaxivity of 4 than for other systems with q = 2 is due to the increase in the molecular dimension of the complex by the conjugation of ATP. The relaxivity of 4 at pH 8.4 (TRIS buffer) decreases to 5.64 mM-1s-1, probably due to a change in the hydration number by the replacement of the coordinated water molecules by TRIS. The r1p relaxivity of 4 in the presence of β-cyclodextrin is 8.97 mM-1s-1 due to the increase in the molecular weight and dimension of the inclusion complex formed by the noncovalent host-guest interaction of the ATP pendant arm with the hydrophobic cavity of β-cyclodextrin. The transverse relaxivity, r2p, of 4 is 7.48 mM-1s-1 (24 MHz and 35±0.1°C). The r2p/r1p ratio of 1.16 indicates that 4 is a T 1-weighted contrast agent. The ATP moiety remains as an extended pendant arm and does not bind with the metal ion, nor does it block the coordination sites for the inner-sphere water molecules. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Ratnakar, S. James,Alexander, Vedhamonickom
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- A new potential contrast agent for magnetic resonance imaging: Synthesis and relaxivity studies of a gadolinium(III) complex of glucose-6-phosphate conjugated 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid
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Synthesis and longitudinal and transverse relaxivities of a gadolinium(III) complex, [Gd(DO3A-Pr-Glu-6-phos)(H2O)2] (4), of glucose-6-phosphate conjugated DO3A (DO3A-Pr-Glu-6-phos = 10-(3-(glucose-6- phosphate)oxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane and DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) are reported. DO3A-Pr-Glu-6-phos (L1) is synthesized by the reaction of bromopropane appended DO3A (3) with glucose-6-phosphate at room temperature. The magnetic moment of 4 is 7.49 BM, which is close to that of the free gadolinium(III) ion. The X- and Q-band epr spectra of 4 at LNT show a broad band with g-values of 2.167 and 2.033, respectively. The higher longitudinal relaxivity of 4 (r1p = 6.99 mM-1 s-1, 24 MHz, 35 °C ± 0.1) than that of [Gd(DOTA)(H2O)]- (r1p = 3.56 mM-1 s-1, 20 MHz, 39°C, pH 7.3) and [Gd(DO3A)(H2O)2] (r1p = 4.8 mM -1 s-1, 20 MHz, 40°C) is attributed to the nature of the glucose-6-phosphate pendant arm. The longitudinal relaxivity of the complex in the presence of β-cyclodextrin increases to 9.62 mM-1 s -1 due to the formation of the inclusion complex. The transverse relaxivity of 4 is 7.02 mM-1 s-1 and the r 2p/r1p ratio of 1.01 indicates that it is a T 1-weighted contrast agent.
- James Ratnakar,Arockia Samy,Alexander
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- Synthesis, relaxivity, and in vitro fluorescence imaging studies of a novel d-f heterometallic trinuclear complex as a potential bimodal imaging probe for MRI and optical imaging
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A new trinuclear heterometallic RuII-GdIII2 complex of 4-aminopyridine appended DO3A (DO3A = 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane) with 2,2′-bipyridine as ancillary ligands is synthesized and its relaxometry and in vitro fluorescence imaging studies are reported. The complex [Ru(bpy)2{Gd(DOTA-AMpy)(H2O)}2]Cl2 (7) exhibits a "per Gd" longitudinal relaxivity (r1p) of 5.80 and 14.30 mM-1 s-1 in aqueous solution and in the presence of HSA, respectively (20 MHz, pH = 7.4, PBS, 37 °C). The complex 7 exhibits an intense 1MLCT absorption band at 480 nm and luminesces at 595 nm with a luminescence quantum yield of 3.2%. The fluorescence microscopy imaging study of HeLa cells incubated with 7 and stained with ethidium bromide and acridine orange confirms that the cells are viable throughout the imaging experiments and its cytotoxicity against HeLa cells, studied by the MTT assay, demonstrates its use for bioimaging studies. HeLa cell lines treated with the complex 7 and stained with Hoechst-33342 showed marked morphological signs of apoptosis in a dose-dependent manner by inducing changes in cell cycle arrest at the G2/M phase. Furthermore, apoptosis of HeLa cells, studied by the DNA ladder assay, indicates apoptotic cell death lending support for the antitumor activity of 7. A molecular docking study reveals that the complex 7 intercalates into the major groove of the DNA stabilized by hydrogen bonding and it binds with HSA by electrostatic- and hydrogen bonding interactions. The relaxometry, luminescence and fluorescence imaging studies indicate that the RuII-GdIII2 complex 7 has a good cell membrane permeability and could be considered as a potential bimodal imaging probe.
- Nithyakumar,Alexander
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- Optimized co-solute paramagnetic relaxation enhancement for the rapid NMR analysis of a highly fibrillogenic peptide
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Co-solute paramagnetic relaxation enhancement (PRE) is an attractive way to speed up data acquisition in NMR spectroscopy by shortening the T 1 relaxation time of the nucleus of interest and thus the necessary recycle delay. Here, we present the rationale to utilize high-spin iron(III) as the optimal transition metal for this purpose and characterize the properties of its neutral chelate form Fe(DO3A) as a suitable PRE agent. Fe(DO3A) effectively reduces the T 1 values across the entire sequence of the intrinsically disordered protein α-synuclein with negligible impact on line width. The agent is better suited than currently used alternatives, shows no specific interaction with the polypeptide chain and, due to its high relaxivity, is effective at low concentrations and in 'proton-less' NMR experiments. By using Fe(DO3A) we were able to complete the backbone resonance assignment of a highly fibrillogenic peptide from α1-antitrypsin by acquiring the necessary suite of multidimensional NMR datasets in 3 h.
- Oktaviani, Nur Alia,Ris?r, Michael W.,Lee, Young-Ho,Megens, Rik P.,De Jong, Djurre H.,Otten, Renee,Scheek, Ruud M.,Enghild, Jan J.,Nielsen, Niels Chr.,Ikegami, Takahisa,Mulder, Frans A. A.
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- Gadobutrol intermediate, preparation method thereof and application of gadobutrol intermediate in preparation of gadobutrol
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The invention discloses a gadobutrol intermediate, a preparation method thereof and application of the gadobutrol intermediate in preparation of gadobutrol. The gadobutrol intermediate is represented by a chemical formula 4 in the specification. The invention also discloses a method for preparing gadobutrol by using the gadobutrol intermediate. The method is reasonable in route design, low in raw material price, high in total yield, high in product purity, low in purification cost and good in economical efficiency, and can fully meet the requirements of industrial production of products.
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Paragraph 0034-0035; 0048-0051
(2022/01/12)
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- NOVEL PROCESS FOR THE PREPARATION OF MACROCYCLIC CHELANT 2,2',2''-(10-(2-HYDROXYPROPYL)-1,4,7,10-TETRA AZACYCLODODECANE-1,4,7-TRIYL) TRIACETIC ACID AND IT'S COMPLEXES WITH PARAMAGNETIC METAL IONS
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The present invention relates to an improved process for the preparation of macrocyclic chelant 2,2',2''-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1). The present invention further relates to the process for the preparation of metal complexes of macrocyclic chelant 2,2',2''-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1) with purity greater than 99.0% by HPLC. The present invention also relates to an improved process for the preparation of gadolinium complex of formula (1a) with macrocyclic chelant 2,2',2''-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1). The present invention further relates to a novel process for the preparation of calcium complex of formula (1b) with macrocyclic chelant 2,2',2''-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1).
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Page/Page column 19
(2020/06/10)
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- A 1, 4, 7, 10 - tetraazacyclododecane - 1, 4, 7 - four three-acetic acid in preparation method (by machine translation)
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A 1, 4, 7, 10 - tetraazacyclododecane - 1, 4, 7 - triacetic acid preparation method. The invention the technical problem to be solved is to provide a high-efficiency, low-cost method for preparing the gadolinium cloth is mellow impurity (DO3A) and [...] complex (DO3A - Gd) process, is used for the quality control of the gadolinium cloth is mellow. In order to [...] (M1) as the starting material, first with the chloroactic acid lithium reaction synthesis impurity DO3A crude, DO3A crude with gadolinium oxide into to get DO3A - Gd, recrystallization of crude product high purity DO3A - Gd. DO3A - Gd under acidic conditions to obtain high purity xie luo DO3A. The reaction process is simple, line clear, without column chromatography, the target compound has high purity and yield, greatly reduces the production of waste gas. (by machine translation)
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Paragraph 0057-0060; 0064-0065; 0070-0072
(2019/02/26)
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- Lanthanide(iii) complexes of monophosphinate/monophosphonate DOTA-analogues: Effects of the substituents on the formation rate and radiolabelling yield
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H4dota and its analogues are routinely used for complexation of lanthanide radioisotopes in nuclear medicine. Many of the radioisotopes have short half-lives and, thus, the complexation rate plays an important role. Notwithstanding that, the relationship between ligand structures and complexation rates is not well understood. Here we report a complexation study of H4dota and its analogues bearing one phosphonate or phosphinate pendant arm. The substituents on the phosphinate group were non-coordinating (-H) or contained another coordinating group (-CH2N(CH2COOH)2, -CH2PO2H2 or -CH2NH2). The basicity of ligands, stability of reaction intermediates, formation rates of CeIII complexes, and 177LuIII radiolabelling were studied. The complexation rates and labelling yields do not show any correlation with ligand basicity. In contrast, the additional chelating group attached to the pendant arm plays an important role. A decreased complexation rate and lower labelling yield were found for compounds bearing an additional amino group, whereas improved properties were found for the compound bearing a geminal bis(phosphinate) pendant arm. It indicates that the introduction of chelating pendant arms with acidic coordinating groups might be a promising strategy to improve radiolabelling of macrocyclic carriers with metal radioisotopes.
- Procházková, Soňa,Kubí?ek, Vojtěch,Kotek, Jan,Vágner, Adrienn,Notni, Johannes,Hermann, Petr
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p. 13006 - 13015
(2018/10/15)
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- Graphene Oxide Cellular Delivery of Hydrophilic Small Molecules
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Unmodified graphene oxide conjugated with hydrophilic small molecules for cellular delivery.
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Paragraph 0083; 0084
(2017/04/04)
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- DOTA analogues with a phosphinate-iminodiacetate pendant arm: Modification of the complex formation rate with a strongly chelating pendant
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The new ligand H6do3aPida combines the macrocyclic DOTA-like cavity and the open-chain iminodiacetate group connected through a coordinating phosphinate spacer. Its acid-base and coordination properties in solution were studied by potentiometry. Thermodynamic coordination characteristics of both chelating units are similar to those reported for H4dota and iminodiacetic acid themselves, respectively, so, macrocyclic and iminodiacetate units behave independently. The formation kinetics of the Ce(iii)-H6do3aPida complex was studied by UV-Vis spectrophotometry. Various out-of-cage intermediates were identified with 1:1, 1:2 and 2:1 ligand-to-metal ratios. The presence of the strongly coordinating iminodiacetate group significantly slows down the metal ion transfer into the macrocyclic cavity and, so, the formation of the in-cage complex is two orders of magnitude slower than that reported for the Ce(iii)-H4dota system. The kinetic inertness of the [Ce(do3aPida)]3- complex towards acid-assisted dissociation is comparable to that of the [Ce(dota)]- complex. The coordination modes of the ligand are demonstrated in the solid-state structure of [Cu4(do3aPida)(OH)(H2O)4]Cl·7.5H2O.
- Procházková, Soňa,Kubí?ek, Vojtěch,B?hmová, Zuzana,Holá, Kate?ina,Kotek, Jan,Hermann, Petr
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p. 10484 - 10497
(2017/08/15)
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- Microwave-Assisted Catalytic Acetylation of Alcohols by Gold-Nanoparticle-Supported Gadolinium Complex
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A gold nanoparticle (AuNP)-supported gadolinium complex (RS-Au-L-Gd) catalyst was prepared through simple chelation of GdCl3 to the surface-bound spacer, 1,4,7-tris(carboxymethyl)-10-(11-mercaptoundecyl)-1,4,7,10-tetraazacyclododecane (HSDO3A). This AuNP-supported Gd complex was found to be a highly effective catalyst for the acetylation of various alcohols and phenol in the presence of acetic anhydride. With a loading of 0.4 mol% of RS-Au-L-Gd, the almost complete transformation can be achieved in 60 s under microwave irradiation conditions. This hybrid catalyst was air stable, water soluble, dissolvable in many organic media, and precipitable. It can be readily recycled more than eight times without any significant loss of its catalytic activity. GRAPHICAL ABSTRACT.
- Chang, Tsao-Ching,Yu, Shuchun Joyce
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supporting information
p. 661 - 672
(2015/10/29)
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- Imaging of Enzyme Activity
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This invention relates to biochemistry and magnetic resonance imaging.
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- Bifunctional Metal Chelating Conjugates
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The present invention is directed to metal chelating conjugates for use as metallopharmaceutical diagnostics or therapeutic agents. Specifically, conjugates of the present invention include a carrier, a metal coordinating moiety, and a urea linkage chemically linking the metal coordinating moiety to the carrier. The carrier is generally utilized for targeting the conjugate to a biological tissue or organ.
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- A PROCESS FOR THE PREPARATION OF 5H,9bH-2a, 4a,7,9a-OCTAHYDROTETRAAZACYCLOOCTA [cd] PENTALENE
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A process for the preparation of 5H,9bH-2a,4a,7, 9a-octahydrotetraazacycloocta[cd]pentalene of formula (I) which comprises the reaction of 1,4,7,10-tetraazacyclododecane with triethyl orthoformate in the absence of solvent and in the presence of an acid catalyst.
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(2008/06/13)
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- MRI GUIDED PHOTODYNAMIC THERAPY FOR CANCER
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Disclosed is a method of therapy used in combination with a diagnostic tool for enhanced photodynamic therapy using MRI, called (magnetic resonance imaging)-guided photodynamic therapy. The methods of the present invention includes administration of MRI contrast agent labeled polymer photosensitizer conjugates, detection and localization of tumor or cancer tissues with contrast-enhanced MRI and specific illumination and treatment of localized target tissues, such as tumors or cancer cells, using laser energy. The delivered laser energy activates the photosentizer accumulated in the target tissue, resulting in treatment. Also disclosed are novel conjugate compounds, such as PLGA-Mce6-DOTA-Gd complexes, having multi-functionality in that the complex may include an MRI contrasting agent linked to a photosensitizing agent.
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Page/Page column 15
(2008/06/13)
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- Pyrene-sensitised near-IR luminescence from ytterbium and neodymium complexes
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Ytterbium and neodymium have been shown to exhibit sensitised emission following excitation of pyrene chromophores. Sensitised emission is demonstrated in self-assembled complexes and in azamacrocycle derivatives bearing pendent pyrene groups. Energy tran
- Faulkner, Stephen,Carrie, Marie-Christine,Pope, Simon J.A.,Squire, Jonathan,Beeby, Andrew,Sammes, Peter G.
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p. 1405 - 1409
(2007/10/03)
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- Imaging thrombus with glycoprotein llb/llla antagonists
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This invention relates to a method of using a radiolabeled small molecule antagonist of the platelet IIb/IIIa receptor for the diagnosis of arterial and venous thrombi.
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- Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
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This invention relates to a method of using radiolabelled and/or radiopharmaceutical small molecule inhibitors of beta-amyloid peptide production for the diagnosis of neurological and other disorders involving APP processing and beta-amyloid production. Furthermore, radiolabelled small molecule inhibitors identified by the methods of the present invention would be useful in the diagnosis of neurological disorders, such as Alzheimer's disease, which involve elevated levels of Aβ peptides.
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- Process for the preparation of 5H, 9bH-2a, 4a, 7, 9a-octahydro-tetraazacycloocta?cd!pentalene
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A process for the preparation of 5H,9bH-2a,4a,7, 9a-octahydrotetraazacycloocta?cd!pentalene of formula (I) STR1 which comprises the reaction of 1,4,7,10-tetraazacyclododecane with triethyl orthoformate in the absence of solvent and in the presence of an acid catalyst.
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- Polyazacycloalkane compounds
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The present invention relates to tribenzylcyclen compounds of formula I STR1 (where R is hydrogen, or a C1-12 alkyl group optionally substituted by hydroxy, alkoxy or aryl groups or R is an amphiphilic aralkyl group comprising a N, S, O or P in
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- Remarkable hydrolysis of phosphodiester by neutral lanthanide(III) DO3A complexes
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The hydrolysis of the 4-nitrophenyl phosphate ester of propylene glycol (HPNP) is catalyzed by neutral lanthanide(III) DO3A complexes. Hydrolysis experiments with complexes of modified ligands where the metal complex was positively charged did not yield i
- Kalesse, Markus,Loos, Andrea
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p. 2063 - 2068
(2007/10/03)
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- 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
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Metal-chelating liquids having the formula STR1 wherein Y is oxygen or STR2 R1 is hydrogen, alkyl, arylalkyl aryl, alkoxy, hydroxyalkyl STR3 wherein G is STR4
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- Manganese (II) chelate manufacture
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The process of this invention for preparing Mn(II) chelate comprises forming the Mn(II) chelate by mixing manganese(II) oxide (insoluble) with an aqueous suspension comprising a molar equivalent or molar excess of the insoluble protonated chelating compound at a temperature of from 20° to 50° C. When the reaction is carried out with a protonated chelating agent in the absence of base, a precipitate of the protonated Mn(II) chelate is formed. A low osmolarity Mn(II) chelate solution can be formed from the precipitates by dissolving them in an aqueous solution of base. When the initial chelate forming reaction is carried out in a solution containing a molar equivalent or excess of sodium hydroxide, a low osmolarity solution of the Mn(II) chelate is directly formed with most chelating agents. Preferred chelating compounds for this process include DPDP, DTPA, DCTA, EDTP, DOTA, DOXA, DO3A and EDTA. The Mn(II) chelate precipitates and low osmolarity solutions formed by the above processes are also aspects of this invention.
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