- Dissociation of CP20 from iron(II)(cp20)3: A pulse radiolysis study
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Deferiprone (CP20), a hydroxypyridine-4-one, is used in iron-chelation therapy. For the iron(III)-/(II)(cp20)3 couple, a standard electrode potential of -620 mV was measured by cyclic voltammetry [Templeton et al., Inorg. Chim. Acta 1996, 245, 199; Merkofer et al., Helv. Chim. Acta 2004, 87, 3021]. On the basis of this value and the overall stability constant for the equilibrium of iron(III) and three CP20 molecules, ligand dissociation ought to take place after reduction of the iron(III)(cp20)3 complex. By pulse radiolysis, we show that hydrated electrons reduce the iron(III)(cp20) 3 complex with a rate constant of k = (6.4 ± 0.3) × 1010 M-1S-1, and that the iron(II)(cp20) 3 complex aquates rapidly. The dissociation of the first two CP20 molecules takes place within a few μs after the pulse. The dissociation rate constant for the last CP20 ligand is (8 ± 1) × 103 S-1. The observation of a dissociation illustrates that, under dilute conditions, iron(II) is not fully complexed by CP20 and could potentially participate in redox cycling to produce oxyradicals. The CO2 - radical does not reduce iron(III)(cp20)3, which indicates that this complex reacts, as expected, very slowly with inner-sphere reductants. Wiley-VCH Verlag GmbH & Co. KGaA, 2006).
- Merkofer, Martin,Domazou, Anastasia,Nauser, Thomas,Koppenol, Willem H.
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- Solid state properties of an oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone, and its acetic acid solvate. I: Physicochemical characterization, intrinsic dissolution rate, and solution thermodynamics
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1,2-Dimethyl-3-hydroxy-4-pyridone (1), a crystalline oral iron chelator, forms an acetic acid solvate (2) on recrystallization from acetic acid and carbon tetrachloride. Compound 2 forms compact prisms, and 1 forms needles from water (mp 274 °C). The X-ray powder diffraction patterns of 1 and 2 differ, indicating distinct solid phases. Compound 2 has an extra DSC endotherm at 82 °C that is accompanied by a weight loss of 29% in TGA, corresponding to the desolvation of a 1:1 acetic acid solvate. Comparison of the solid-state 13C NMR of 1 and 2 revealed two additional peaks for 2 at 20.3 and 175.6 ppm, characteristic of -CH3 and -COOH, respectively, of acetic acid. The integrated intensities confirmed the 1:1 stoichiometry between 1 and acetic acid. However, 2 underwent desolvation in air at 25 °C as suggested by a change in its appearance to opaque crystals and as confirmed by X-ray powder diffraction, DSC, and TGA. Desolvation of 2 at 25 °C was a zero-order process with a rate constant of 6.9 μmol·h-1. X-ray powder diffraction showed that crystals or compacted discs of 1 are converted to 2 in contact with glacial acetic acid (A), whereas crystals or discs of 2 are converted to 1 in contact with water. The intrinsic dissolution rate (J) and the apparent solubility (C(s)) of compacted discs of 1 and 2 were measured in water at 25 °C, and the following relations were determined: J(2)/J(1) = 1.39 and C(s)(2)/C(s)(1) = 1.70. From solubility measurements, the standard Gibbs free energy of transfer (ΔG°, kcal·mol-1) at 25 °C with respect to the molar concentration scale are as follows: 1 to H2O, 5.40; 2 to H2O, 2O, -10.48 (from literature data). Using solution calorimetry, the corresponding enthalpy changes (ΔH°, kcal·mol-1) at 25 °C were measured: 1 to H2O, 18.7; 2 to H2O, 30.2; 1 to A, 17.3; 2 to A, 29.4; A to H2O, -1.1. A thermodynamic cycle shows that these values are self-consistent. The positive enthalpy changes indicate that the dissolution of 1 and 2 in water or A is entropy driven. Furthermore, the dissolution of 2 in water or A is more endothermic than that of 1 by only ~1 kJ·mol-1. Use of isotonic phosphate buffered saline (pH 7.4) instead of water gave similar thermodynamic values (within 5%), and the main conclusions were unaltered.
- Chan,Venkataram,Grant,Rahman
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- Interaction between the low molecular mass components of blood serum and the VO(IV)-DHP system (DHP = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone)
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In order to estimate the impact of the low molecular mass (l.m.m.) VO(IV) binders of blood serum on the potentially insulin-enhancing drug [VO(DHP)2] [DHP = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone], the speciation in the binary system VO(IV)-DHP and in the ternary systems VO-DHP-ligand B (B = oxalate, lactate, citrate or phosphate) was studied by pH-potentiometry at 25.0°C and at an ionic strength I = 0.2 mol dm-3 (KCl). The binding modes of the complexes formed were determined by spectroscopic (electronic absorption and EPR) techniques. DHP was found to form stable mono and bis complexes via the coordination of (O,O) chelate(s). Through displacement of the oxo group of VO(IV), the tris complex is also formed, especially at a high excess of ligand. The results in the ternary systems demonstrate that, at physiological pH, none of the B ligands can compete with DHP; [VO(DHP)2] therefore seems to remain almost completely intact, even in the presence of citrate, the strongest competitor among these B ligands. These findings indicate that, for DHP, unlike maltol or picolinic acid, ternary complex formation and thus transformation reactions with the l.m.m. binders of biofluids, is almost negligible. From among the three carrier molecules, only DHP can effeciently compete with serum transferrin for binding of VO(IV).
- Buglyo, Peter,Kiss, Tamas,Kiss, Erzsebet,Sanna, Daniele,Garribba, Eugenio,Micera, Giovanni
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- First insights into the novel class of organometallic compounds bearing a bidentate selenopyridone coordination motif: Synthesis, characterization, stability and biological investigations
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A series of seven piano–stool complexes featuring selenopyridones as Se,O-chelating ligands was synthesized and characterized. The resulting complexes bear either a p-cym Ru/Os or Cp* Rh/Ir fragment attached to a bidentate selenopyridone ligand. In accordance with recent findings for closely related thiopyridone complexes, dimerization in protic solvents was observed for these compounds. However, these organometallics revealed surprises regarding stability, as well as biological activity. In contrast to analogous thiopyridone organometallics, some of the synthesized complexes were prone to quick ligand dissociation. However, four examples exhibited sufficient stability in aqueous solution to justify further biological investigations. Therefore, MTT assays were carried out for the stable derivatives in three different cancer cell lines. Cytotoxicity trends based on the utilized metal center of the organometallic moiety were observed and compared to the corresponding thio-analogs.
- Gajic, Natalie,Harringer, Sophia,Hejl, Michaela,Jakupec, Michael A.,Kandioller, Wolfgang,Keppler, Bernhard K.,Matzinger, Manuel
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- Synthesis, Modification, and Biological Evaluation of a Library of Novel Water-Soluble Thiopyridone-Based Organometallic Complexes and Their Unexpected (Biological) Behavior
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A series of 16 dinuclear thiopyridone-based organometallics with excellent water solubility, increased stability and remarkable cytotoxicity were synthesized and characterized. The complexes of this work formed dimeric species featuring a double positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayed higher antiproliferative activity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line. Insights into their behavior in biological systems were gathered by means of amino-acid interaction studies, cytotoxicity tests in 3D spheroid models, laser ablation, cellular accumulation measurements, as well as cell cycle experiments.
- Gajic, Natalie,Happl, Barbara,Harringer, Sophia,Hejl, Michaela,Jakupec, Michael A.,Kandioller, Wolfgang,Kast, Caroline,Keppler, Bernhard K.,Koellensperger, Gunda,Legin, Anton A.,Ozenil, Marius,Roller, Alexander,Schweikert, Andreas,Wernitznig, Debora
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- Discovery of N-Aryl-pyridine-4-ones as Novel Potential Agrochemical Fungicides and Bactericides
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A series of N-aryl-pyridine-4-one derivatives were designed and synthesized using maltol and antidesmone as lead compounds, and then their fungicidal/bactericidal activities and possible mechanism of action against Colletotrichum musae were explored. Most of these compounds exhibited significant fungicidal activity in vitro. Especially, compound 23 has more than 90% inhibitory activity against nine plant pathogenic fungi at 50 μg mL-1, which is superior to azoxystrobin. Moreover, an in vivo bioassay also demonstrated that compound 23 exhibited high-efficiency broad-spectrum antifungal activity and can effectively control postharvest diseases of mango. In addition, it was found that compounds 22 and 23 can also effectively control rice bacterial leaf blight in pot experiments, which was even more effective than zhongshengmycin. Preliminary mechanism studies revealed that compound 23 may cause cell membrane and mitochondria destruction. These findings indicate that compound 23 can be used to develop potential agrochemical fungicides and bactericides.
- Yu, Xiuqiang,Zhu, Xinyue,Zhou, Yang,Li, Qinglin,Hu, Zhan,Li, Ting,Tao, Jun,Dou, Menglan,Zhang, Meng,Shao, Yu,Sun, Ranfeng
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p. 13904 - 13913
(2019/12/24)
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- Application of 1-aryl-4-pyridone compound
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The invention discloses application of a 1-aryl-4-pyridone compound, and provides application of a compound of a structure of a formula (I) shown in the description in inhibiting activity of plant pathogenic bacteria. The compound of the structure of the formula (I) shown in the description has outstanding broad-spectrum antifungal activity upon plant pathogenic bacteria in agricultural production, and meanwhile, has a prevention and treatment effect on bacterial disease of crops. In-vivo biological assay shows that the compound of the structure of the formula (I) shown in the description hasa prevention and control effect greater than 95% on cucumber downy mildew, cucumber target leaf spot, wheat scab and tomato gray mold. Meanwhile, results of postharvest fresh-keeping tests of mangos show that the compound is capable of effectively controlling postharvest diseases of mangos and in addition, prolonging the fresh-keeping time of the mangos. In addition, results show that the compoundis also capable of effectively controlling bacterial leaf blight of rice in pot experiments, and is more effective than a commercial fungicide zhongshengmycin. In conclusion, the 1-aryl-4-pyridone derivative of the formula (I) shown in the description has broad-spectrum plant pathogenic fungus resistance and bacterial activity, and is a type of lead compounds with wide bioactivity.
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Paragraph 0071-0074
(2020/01/12)
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- Chemical compound applicable to preparation of cleaning agent for heat-supply and heating system and preparation method thereof
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The invention discloses a chemical compound, as shown in a formula I, applicable to preparation of a cleaning agent for a heat-supply and heating system, and a preparation method and application thereof. According to the invention, experiment results show that the chemical compounds as shown in the formula I can quickly and effectively dissolve and chelate calcium ions and maintain good solubility. The cleaning agent used for the heat-supply and heating system and prepared from the chemical compound as shown in the formula I can effectively and thoroughly clean various rust spots, dirts and cured substances which are stuck to a boiler and a pipeline, reduces the scaling speed of the boiler and the pipeline, and can significantly improve the heat efficiency of the boiler and the pipeline.
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Paragraph 0019
(2017/01/19)
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- Synthesis of oxovanadium complexes and their apoptosis-inducing activity in leukemia cells
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Vanadium complexes with different ligands were synthesized and evaluated for antiproliferative activity on U937 cells. The alkyl chain length of the ligands affected the antiproliferative activity, and two complexes - 3b and 4 - exhibited strong activities with IC50 values of 6.02 and 3.90 μM respectively. Annexin V staining and DNA ladder formation indicated that these complexes induced apoptosis in U937 cells.
- Yamaguchi, Tomoko,Watanabe, Shinya,Matsumura, Yuriko,Tokuoka, Yoshikazu,Yokoyama, Akihiro
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p. 508 - 512
(2012/05/19)
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- Investigation of self-immolative linkers in the design of hydrogen peroxide activated metalloprotein inhibitors
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A series of self-immolative boronic ester protected methyl salicylates and metal-binding groups with various linking strategies have been investigated for their use in the design of matrix metalloproteinase proinhibitors.
- Jourden, Jody L. Major,Daniel, Kevin B.,Cohen, Seth M.
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supporting information; experimental part
p. 7968 - 7970
(2011/08/07)
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- STIMULUS-TRIGGERED PRODRUGS
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Set forth herein, inter alia, are compositions and methods for treating diseases with prodrugs. Provided herein are prodrug compositions for inhibiting the function of proteins, compositions and methods for treating diseases associated with oxidative compounds, oxidatively-sensitive prodrugs of inhibitors of metalloproteases. and methods of inhibiting metalloproteases using oxidatively-sensitive prodrugs.
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Page/Page column 54-56
(2012/01/13)
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- In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease
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Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy, and in one case by X-ray crystallography. The Cu2+ complex of a novel 3-hydroxy-4-pyridinone was synthesized and characterized by IR and X-ray crystallography, showing the ability of these compounds to chelate potentially toxic metal ions. An MTT cytotoxicity assay of a selected glycosylated compound showed a relatively low toxicity of IC50 = 570 ± 90 μM in a human breast cancer cell line. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.β-glucosidase, and for one compound kcat and Km were determined to be 19.8 s-1 and 1.52 mM, respectively. Trolox Equivalent Antioxidant Capacity (TEAC) values were determined for the free pyridinones, indicating the good antioxidant properties of these compounds. Metal-Aβ1-40 aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands. The Royal Society of Chemistry 2010.
- Green, David E.,Bowen, Meryn L.,Scott, Lauren E.,Storr, Tim,Merkel, Michael,Boehmerle, Karin,Thompson, Katherine H.,Patrick, Brian O.,Schugar, Harvey J.,Orvig, Chris
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experimental part
p. 1604 - 1615
(2010/06/20)
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- An extremely high insulin-mimetic activity of bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridinolato)zinc(II) complex
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Vanadyl and zinc(II) complexes with VO(O2S2) and Zn(O2S2) coordination mode, respectively, were synthesized. Among them, bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridinolato)zinc(II) complex exhibited an extremely high insulin-mimetic activity (IC50 = 0.04 mM when IC50 value of a positive control, VOSO4 was estimated to be 1.0 mM) compared to vanadyl and zinc(II) complexes reported previously.
- Katoh, Akira,Tsukahara, Takeshi,Saito, Ryota,Ghosh, Kallol K.,Yoshikawa, Yutaka,Kojima, Yoshitane,Tamura, Asuka,Sakurai, Hiromu
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p. 114 - 115
(2007/10/03)
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- Efficient syntheses of N-alkyl-3-hydroxy-2-methyl-4(1H)-pyridinones from carbohydrate precursors
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N-alkyl-3-hydroxy-2-methyl-4(1H)-pyridinones can be synthesised in reasonable yield from either 1-(3-hydroxy-2-furanyl)ethanone or O- galactosylisomaltol. Since these carbohydrate precursors can be produced from the disaccharide, α-D-lactose, a simple and inexpensive transformation into pyridinones is possible.
- Fox, Raymond C.,Taylor, Paul D.
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p. 989 - 1001
(2007/10/03)
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- 3-Hydroxy-4-pyrones as precursors of 4-methoxy-3-oxidopyridinium ylides. An expeditious entry to highly substituted 8-azabicyclo[3.2.1]octanes
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3-Hydroxy-4-pyridones, which are easily prepared from commercially available 3-hydroxy-4-pyrones, can be readily transformed into 4-methoxy-3-oxidopyridinium ylides by treatment with methyl trifluoromethanesulfonate and subsequent deprotonation with a non-nucleophilic base. These ylides are capable of undergoing cycloaddition to several electron-deficient alkenes, thus allowing the synthesis of highly functionalized azabicyclo[3.2.1]octane moieties. The rich substitution patterns of these frameworks might allow their divergent conversion to a variety of natural and non-natural tropane alkaloids.
- Rumbo, Antonio,Mourino, Antonio,Castedo, Luis,Mascarenas, Jose L.
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p. 6114 - 6120
(2007/10/03)
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- Development and Application of a Continuous Microwave Reactor for Organic Synthesis
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A laboratory-scale continuous microwave reactor (CMR) has been developed and used to conduct organic syntheses routinely, rapidly, and safely in a range of solvents, under pressures up to 1400 kPa and at temperatures up to 200 deg C.Advantages and applications of the CMR are discussed, along with the rationale for the design.Reactions carried out with the CMR included nucleophilic substitution, addition, esterification, transesterification, acetalization, amidation, base- and acid-catalyzed hydrolysis, isomerization, decarboxylation, and elimination.Name reactions included the Michael addition, Hofmann degradation, Williamson ether synthesis, and the Mannich, Finkelstein, Baylis-Hillman, and Knoevenagel reactions.
- Cablewski, Teresa,Faux, Alan F.,Strauss, Christopher R.
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p. 3408 - 3412
(2007/10/02)
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- Stabilization of organic compounds
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Admixture of insulin and a hydroxypyridone being: (1) a 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, cycloalkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic acyl, alkoxy, cycloalkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, cycloalkoxy, aliphatic ester, halogen or hydroxy group, or a salt thereof.
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- Process for producing pyrid-4-ones
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Substituted-3-hydroxy-pyrid-4-ones, derivatives thereof, and salts thereof are produced by reacting subsituted-3-hydroxypyr-4-one with ammonia or a non-sterically hindered primary amine usually in the presence of a solvent such as water. Also disclosed are novel derivatives of 2-ethyl-3-hydroxypyrid-4-one.
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- Physical and structural studies of N-substituted-3-hydroxy-2-methyl-4(1H)-pyridinones
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A series of 3-hydroxy-2-methyl-4(1H)-pyridinones has been prepared with the sunstituents H, CH3, n-C6H11, and CH2CH2NH2 at the ring N.The dipyridinone 1,6-bis(3-hydroxy-2-methyl-4(1H)-pyridinon-1-yl)hexane has also been synthesized.The products with H and CH3 subtituents have been studied by single crystal X-ray diffraction.Crystals of 3-hydroxy-2-methyl-4-pyridinone are monoclinic, a=6.8351(4), b=10.2249(4), c=8.6525(4) Angstroem, β=105.215(4) deg, Z=4,space group P21/n and those of 3-hydroxy-1,2-dimethyl-4-pyridinone are orthorhombic, a=7.3036(4), b=13.0490(6), c=13.7681(7) Angstroem, Z=8, space group Pbca.Both structures were solved by direct methods and were refined by full-matrix least-squares procedures to R=0.037 and 0.044 for 914 and 857 reflections with I>/=3?(I), respectively.Bond lengths and angles in the compounds were normal.All the compounds have been studies by mass spectrometry, and by infrared and proton nmr spectroscopies.The importance of hydrogen bonding to both the solution and solid state properties of these compounds has been confirmed by these techniques.
- Nelson, William O.,Karpishin,Timothy B.,Rettig, Steven J.,Orvig, Cris
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p. 123 - 131
(2007/10/02)
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- New synthetic approach and iron chelating studies of 1-alkyl-2-methyl-3-hydroxypyrid-4-ones
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The major diseases of iron metabolism are iron deficiency anaemia, which could be treated using Fe2+ or Fe3+ salt supplements, and iron overload, which could arise either from an increased gastrointestinal absorption of iron or from recurrent blood transfusions. While the former form of iron overload could be treated by phlebotomy the latter requires the use of a chelator. Desferrioxamine is the only clinically available chelator for the treatment of iron overload but its use worldwide is limited because it is expensive and orally inactive. Several α-ketohydroxy heteroaromatic chelators have been synthesised and tested for their iron binding properties at physiological pH. The synthetic route involves the benzylation of the hydroxyl group of maltol using benzyl chloride, the conversion of the benzylated maltol to the 1-alkyl benzylated pyridine derivative by introducing the corresponding alkylamine in alkaline conditions and the cleavage of the benzyl group in acid to form the 1-alkyl-2-methyl-3-hydroxypyrid-4-one. All the chelators are water soluble and stable at a wide range of pH, forming stable, water soluble, coloured iron complexes with a molar ratio of approximately 3 chelator:1 iron at pH 7.4 and lower molar ratio of chelators to iron complexes at acidic pH. When the 1-methyl, 1-ethyl and 1-propyl, -2-methyl-3-hydroxypyrid-4-ones were mixed at pH 7.4 with transferrin, ferritin and haemosiderin substantial amounts of iron were released. The low cost of synthesis, the strong iron binding properties of these chelators and their other in vitro and in vivo iron mobilising effects increase the prospects of their use in many aspects of iron metabolism and the possible treatment of related diseases particularly iron overload.
- Kontoghiorghes,Sheppard,Chambers
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p. 1099 - 1102
(2007/10/02)
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- Iron complexes of hydroxy pyridones useful for treating iron deficiency anemia
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Pharmaceutical compositions containing an iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are also replaced by an aliphatic hydrocarbon group, are of value for the treatment of iron deficiency anemia.
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