- 'Unconventional' coordination chemistry by metal chelating fragments in a metalloprotein active site
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The binding of three closely related chelators: 5-hydroxy-2-methyl-4H- pyran-4-thione (allothiomaltol, ATM), 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, TM), and 3-hydroxy-4H-pyran-4-thione (thiopyromeconic acid, TPMA) to the active site of human ca
- Martin, David P.,Blachly, Patrick G.,Marts, Amy R.,Woodruff, Tessa M.,De Oliveira, César A. F.,McCammon, J. Andrew,Tierney, David L.,Cohen, Seth M.
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- Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity
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A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β1-42 (Aβ1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
- Bai, Renren,Gu, Jinping,Guo, Jianan,Jiang, Xiaoying,Lv, Yangjing,Mi, Zhisheng,Shi, Yuan,Xie, Yuanyuan,Yao, Chuansheng,Zhang, Changjun,Zhou, Tao
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- Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative
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The invention discloses a coumarin hybrid pyridinone amide derivative and a preparation method and application thereof. The coumarin hybrid pyridinone amide derivative and pharmacologically acceptablesalt thereof are shown in the formula (I) and the formula (II), and the derivative can be used for preparing drugs for resisting the Alzheimer's disease, the Parkinson's disease or treating other diseases or symptoms by suppressing monoamine oxidase, chelating metallic iron ions, resisting A and resisting oxidation.
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Paragraph 0062; 0063; 0064
(2020/02/27)
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- Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds
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The invention discloses coumarin/pyridone heterozygous derivatives represented by a formula (I) shown in the description or a pharmaceutically-acceptable salt of the derivatives. The preparation method of the coumarin/pyridone heterozygous derivatives comprises the following steps: one pyridone derivative represented by a formula 3 shown in the description is obtained by a series of synthesis by using one hydroxypyrone with different substituent groups represented by a formula 1 shown in the description as a raw material; and a compound represented by a formula 4 shown in the description is subjected to a condensation reaction to obtain a compound represented by a formula 5 shown in the description, one-step bromination is performed to obtain a compound represented by a formula 6 shown inthe description, the compound represented by the formula 6 and the pyridone derivative represented by the formula 3 are subjected to a one-step nucleophilic substitution reaction to obtain a compoundrepresented by a formula 7 shown in the description, and finally an alkyl protecting group in a pyridone structure is removed to obtain one target compound represented by the formula (I). The compounds provided by the invention are a novel series of single-molecular multi-target series drugs, and have iron chelation, targeted MAO-B inhibitory activity, antioxidant activity, unique advantages for an Alzheimer disease with complicated pathogenesis, a clear mechanism of action and excellent activity.
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Paragraph 0057-0059; 0069; 0072
(2019/10/01)
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- Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease
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A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC50 value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.
- Zhang, Changjun,Yang, Ke,Yu, Sihang,Su, Jing,Yuan, Shengli,Han, Jiaxin,Chen, Yan,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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p. 367 - 382
(2019/07/19)
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- Synthetic method for amino-containing hydroxypyridone compound
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The invention discloses a synthetic method for an amino-containing 3-hydroxypyridine-4-ketone iron chelating agent as shown in a formula (III) which is described in the specification. The synthetic method comprises the following steps: with methyl-protected azido hydroxypyridone as shown in a formula (I) which is described in the specification as a raw material, allowing the methyl-protected azido-hydroxypyridine to generate reduction and demethylation reactions under the protection of boron tribromide as shown in a formula (II) which is described in the specification, a solvent A and gas B, after completion of the reactions, carrying out quenching with a solvent C, and carrying out post-treatment so as to obtain the amino-containing 3-hydroxypyridine-4-ketone compound as shown in the formula (III). Compared with a conventional method, the synthetic method provided by the invention adopts a boron tribromide reagent with mild reaction conditions, avoids the use of a metal catalyst, andhas simple and convenient operation and high reaction yield.
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Paragraph 0064-0066
(2018/09/08)
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- Macromolecular iron-chelators via RAFT-polymerization for the inhibition of methicillin-resistant Staphylococcus aureus growth
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A series of linear poly (glycidyl methacrylate) (PGMA) polymers were synthesized via RAFT polymerization and conjugated with amine-containing 3-hydroxypyridin-4-ones (HPOs) to generate a panel of HPO-containing materials with controlled structures and spe
- Li, Junpei,Olaleye, Eniola D.,Kong, Xiaole,Zhou, Tao,Ma, Yongmin,Jurach, Jagoda,Al Rugaie, Osamah,Hider, Robert C.,Zhang, Guoqing,Alsam, Selwa,Abbate, Vincenzo
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supporting information
p. 64 - 72
(2016/02/19)
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- Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids
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A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).
- Andayi, Warren A.,Egan, Timothy J.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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p. 642 - 646
(2013/07/26)
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- Total syntheses and biological evaluation of 3-O-methylfunicone and its derivatives prepared by TMPZnCl·LiCl-mediated halogenation and carbonylative stille cross-coupling
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The total syntheses of the natural product 3-O-methylfunicone (1), a member of the funicone class of compounds, and its derivatives is reported. The key reactions in the construction of the biaryl ketone core are a regioselective TMPZnCl·LiCl halogenation and a carbonylative Stille cross-coupling reaction. In addition, the inhibitory activities of the funicones against Y-family DNA polymerase κ (pol κ) and polymerase η (pol η) were determined. We found that 1 and 12 exhibit inhibitory activity against pol η and 1 also against pol κ. The total syntheses of the natural product 3-O-methylfunicone and its derivatives has been accomplished. The key reactions are TMPZnCl·LiCl-mediated iodination and a carbonylative Stille cross-coupling reaction. In addition, the inhibitory effect of the synthesized compounds have been evaluated against Y-family DNA polymerases κ and η by primer extension experiments. Copyright
- Ehrlich, Michael,Carell, Thomas
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supporting information
p. 77 - 83
(2013/03/13)
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- Prediction of 3-hydroxypyridin-4-one (HPO) hydroxyl pKa values
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As an aid in optimising the design of 3-hydroxypyridin-4-ones (HPOs) intended for use as therapeutic Fe3+ chelating agents, various quantum mechanical (QM) and semi-empirical (QSAR) methods have been explored for predicting the pKa values of the hydroxyl groups in these compounds. Using a training set of 15 HPOs with known hydroxyl pKa values, reliable predictions are shown to be obtained with QM calculations using the B3LYP/6-31+G(d)/CPCM model chemistry (with Pauling radii, and water as solvent). With this methodology, the observed hydroxyl pKa values for the training set compound are closely matched by the predicted pKa values, with the correlation between the observed and predicted values giving r2 = 0.98. Predictions subsequently made by this method for a test set of 48 HPOs of known hydroxyl pKa values (11 of which were determined experimentally in this study), gave predicted pKa values accurate to within ±0.2 log units. In order to further investigate the predictive power of the method, two novel HPOs were synthesised and their hydroxyl pKa values were determined experimentally. Comparison of these predicted pKa values against the measured values gave absolute deviations of 0.13 (10.18 vs. 10.31) and 0.43 (5.58 vs. 5.15).
- Chen, Yu-Lin,Barlow, Dave J.,Kong, Xiao-Le,Ma, Yong-Min,Hider, Robert C.
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scheme or table
p. 6549 - 6557
(2012/09/11)
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- Targeting the lysosome: Fluorescent iron(III) chelators to selectively monitor endosomal/ lysosomal labile iron pools
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Iron-sensitive fluorescent chemosensors in combination with digital fluorescence spectroscopy have led to the identification of a distinct subcellular compartmentation of intracellular redox-active "labile" iron. To investigate the distribution of labile iron, our research has been focused on the development of fluorescent iron sensors targeting the endosomal/lysosomal system. Following the recent introduction of a series of 3-hydroxypyridin-4-one (HPO) based fluorescent probes we present here two novel HPO sensors capable of accumulating and monitoring iron exclusively in endosomal/lysosomal compartments. Flow cytometric and confocal microscopy studies in murine macrophages revealed endosomal/lysosomal sequestration of the probes and high responsiveness toward alterations of vesicular labile iron concentrations. This allowed assessment of cellular iron status with high sensitivity in response to the clinically applied medications desferrioxamine, deferiprone, and deferasirox. The probes represent a powerful class of sensors for quantitative iron detection and clinical real-time monitoring of subcellular labile iron levels in health and disease.
- Fakih, Sarah,Podinovskaia, Maria,Kong, Xiaole,Collins, Helen L.,Schaible, Ulrich E.,Hider, Robert C.
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experimental part
p. 4539 - 4552
(2009/07/04)
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- Design, synthesis, physicochemical properties, and evaluation of novel iron chelators with fluorescent sensors
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The synthesis of a range of novel 3-hydroxypyridin-4-ones and 3-hydroxypyran-4-ones linked with different coumarin substituents is described. These compounds have been developed in order to provide a series of molecular probes for the quantification of intracellular labile iron pools. An evaluation of the effect of iron(III) on fluorescence intensity was undertaken. Chelation of iron(III) causes quenching of fluorescence. The relationship between iron(III) concentration and the extent of fluorescence quenching indicates that the metal is chelated in a complex with a metal-to-ligand stoichiometry of 1:3. The fluorescence of hydroxypyridinone compounds was found to be more efficiently quenched by iron(III) than were the hydroxypyranones. The metal-to-ligand stoichiometry at which maximum quenching is observed was found to depend on the site at which coumarin is attached. The efficiency of fluorescence quenching by iron(III) is markedly influenced by solvent polarity and pH. The permeability of two representative fluorescent chelators across human erythrocyte ghost membranes was investigated. The rate of permeability for a series of probes was found to be related to the corresponding ClogP values.
- Ma, Yongmin,Luo, Wei,Quinn, Peter J.,Liu, Zudong,Hider, Robert C.
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p. 6349 - 6362
(2007/10/03)
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- Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
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Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
- Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
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p. 4906 - 4916
(2007/10/03)
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- Preparation of 3-Hydroxy- and 3-Methoxy-N-heteroaryl-2-methyl-4-pyridones
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A number of new 3-hydroxy- and 3-methoxy-2-methyl-4-pyridones substituted on the nitrogen atom with selected heterocycles has been prepared. Novel chelating properties of the hydroxy-compounds are expected.
- Jakopcic, Kresimir,Mintas, Mladen,Isufi, Islam
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p. 429 - 433
(2007/10/02)
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- Pyridones as potential antitumor agents II: 4-pyridones and bioisosteres of 3-acetoxy-2-pyridone
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Pyridone structural requirements for activity against murine P-388 leukemia have been extended to isosteric analogs of 3-hydroxy-4-pyridone, a compound previously found to have activity. An amino group can be substituted for the 3-hydroxyl function with retention of activity. A sulfur, but not an amino function, can replace the lactam oxygen in the 2-position. Relocation of the lactam oxygen from the 2- to the 4-position in the pyridine ring also produces active pyridones, including 2-methyl-3-acetoxy-4-pyridone. This compound, which has a T/C value of 179%, is the most active material discovered thus far in the pyridone studies.
- Hwang,Proctor,Driscoll
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p. 1074 - 1076
(2007/10/02)
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- Shoyu (Soy Sauce) Flavor Components: Acidic Fractions and the Characteristic Flavor Component
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From the volatile flavor concentrate of shoyu, acidic I and acidic II fractions were separated.Shoyu was also directly extracted with CH2Cl2 in order to cover the components that were not obtained by the above method, and the extract was separated into ten (A-J) fractions.C-I fractions were acidic ones.The above fractions were successively analyzed by gas chromatography and combined gas chromatography-mass spectrometry.Consequently, 93 components were identified, 36 of which have not been reported previously as constituents of shoyu.The identified compounds were 15 alcohols, 15 carbonyls, 9 esters, 4 lactones, 6 furans, 3 furanones, 5 pyrones, 7 phenols, 13 acids and 16 other compounds.Organoleptically, the caramel-like aroma compounds among them are important for the characteristic flavor of shoyu. 4-Hydroxy-2(or 5)-ethyl-5-5(or 2)-methyl-3(2H)-furanone (HEMF) and 4-hydroxy-5-methyl-3(2H)-furanone seem to be important, and particularly, in view of the content and the organoleptic property, HEMF is concluded to be the main and most important constituent of the characteristic flavor of shoyu.
- Nunomura, Nobutake,Sasaki, Masaoki,Yokotsuka, Tamotsu
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p. 339 - 352
(2007/10/02)
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