- Synthesis of hydrolysis-resistant pyridoxal 5′-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin
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A set of phosphonic acid derivatives (1-4) of pyridoxal 5′-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79 μM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75 ? resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents.
- Knobloch, Gunnar,Jabari, Nauras,Stadlbauer, Sven,Schindelin, Hermann,K?hn, Maja,Gohla, Antje
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- Bifunctional pyridoxal derivatives as efficient bioorthogonal reagents for biomacromolecule modifications
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Two types of pyridoxal analogs, azido pyridoxal (PL-N3) and carboxyl pyridoxal (PL-COOH), were developed as novel bifunctional bioorthogonal molecules. These molecules showed fast imine formation with hydrazinyl groups and stable covalent linkages via azido/carboxyl groups, and thus were of great use for site-specific peptide and protein modifications.
- Duan, Yuting,Fei, Jiayue,Li, Wei,Mao, Xianxian,Tian, Hongyan,Wang, Xiaojian,Wang, Yuntao,Zhu, Shiyu,Zou, Juan
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- Synthesis, molecular docking and spectroscopic studies of pyridoxine carbamates as metal chelator
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Herein, we have reported synthesis, characterization, molecular docking and metal chelating potential of various pyridoxine carbamates for biometals (copper, zinc and iron) via spectroscopic methods. All the derivatives showed metal chelation ability and 4g was found the most potent metal chelator, having a binding stoichiometry of 1:1 with Cu+2 ion. Interactions of metal with ligand 4g was studied and the participation of both carbamate and free –OH group in complex formation was confirmed. All the synthesized compounds showed druglikeness properties, passing the lipinki's Rule of five. According to Pass study 4a, 4b, 4d and 4h to show significant nootropic activity (Pa > 0.60) in comparison to donepezil. Fluorescence quenching study and analysis with BSA with 4g showed static quenching mechanism. Molecular docking showed probable site of binding with least binding energy of ?5.9 kcal mol?1. The compound 4g also showed binding with acetylcholinesterase in UV–Vis spectrum. The study concludes that pyridoxine-carbamates are biometal chelator, possess other properties also like drug likeness, binding with BSA and acetylcholinetersae.
- Pal, Tiyas,Patil, Pooja,Sharma, Abha
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- Chemical synthesis of 5’-β-glycoconjugates of vitamin B6
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Various 5’-β-saccharides of pyridoxine, namely the mannoside, galactoside, arabinoside, maltoside, cellobioside and glucuronide, were synthesized chemically according to KOENIGS-KNORR conditions using α4,3-O-isopropylidene pyridoxine and the respective acetobromo glycosyl donors with AgOTf (3.0 eq.) and NIS (3.0 eq.) as promoters at 0 °C. Furthermore, 5’-β-[13C6]-labeled pyridoxine glucoside (PNG) was prepared starting from [13C6]-glucose and pyridoxine. Additionally, two strategies were examined for the synthesis of 5’-β-pyridoxal glucoside (PLG).
- Bachmann, Thomas,Schnurr, Christian,Zainer, Laura,Rychlik, Michael
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- SAR of non-hydrolysable analogs of pyridoxal 5′-phosphate against low molecular weight protein tyrosine phosphatase isoforms
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Kinases and phosphatases are key enzymes in cell signal transduction pathways. Imbalances in these enzymes have been linked to numerous disease states ranging from cancer to diabetes to autoimmune disorders. The two isoforms (IFA and IFB) of Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) appear to play a role in these diseases. Pyridoxal 5′-phosphate (PLP) has been shown to act as a potent but, impractical micromolar inhibitor for both isoforms. In this study, a series of non-hydrolysable phosphonate analogs of PLP were designed, synthesized and tested against the two isoforms of LMW-PTP. Assay results demonstrated that the best inhibitor for both isoforms was compound 5 with a Kis of 1.84 μM (IFA) and 15.6 μM (IFB). The most selective inhibitor was compound 16, with a selectivity of roughly 370-fold for IFA over IFB.
- DeSouza, Shirin R.,Flynn, Rebecca S.,Jakubowski, Henry V.,Marshall, Quinlen F.,McIntee, Edward J.,Olson, Maxwell C.,Sinner, Erica K.,Tinucci, Samantha L.
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supporting information
(2020/07/21)
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- Pyridoxine-resveratrol hybrids as novel inhibitors of MAO-B with antioxidant and neuroprotective activities for the treatment of Parkinson's disease
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A series of pyridoxine-resveratrol hybrids were designed and synthesized as monoamine oxidase B inhibitors for the treatment of Parkinson's disease. Most of them exhibited potent inhibitory activities on MAO-B with high selectivity. Specifically, compounds 12a, 12g and 12l showed the most excellent inhibition to hMAO-B with the IC50 values of 0.01 μM, 0.01 μM and 0.02 μM, respectively. Further reversibility study demonstrated that 12a and 12l were reversible and 12g was irreversible MAO-B inhibitors. Molecular docking studies of MAO revealed the binding mode and high selectivity of these compounds with MAO-B. In addition, these three representative compounds also exhibited low cytotoxicity and excellent neuroprotective effect in the test on H2O2-induced PC-12 cell injury. Moreover, 12a, 12g and 12l showed good antioxidant activities and high blood-brain barrier permeability. Overall, all of these results highlighted 12a, 12g and 12l were potential and excellent MAO-B inhibitors for PD treatment.
- Cao, Zhongcheng,Deng, Yong,Li, Wei,Shi, Yichun,Song, Qing,Yang, Xia,Zhang, Li
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- Chemical glucosylation of pyridoxine
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The chemical synthesis of pyridoxine-5′-β-D-glucoside (5′-β-PNG) was investigated using various glucoside donors and promoters. Hereby, the combination of α4,3-O-isopropylidene pyridoxine, glucose vested with different leaving and protecting groups and the application of stoichiometric amounts of different promoters was examined with regards to the preparation of the twofold protected PNG. Best results were obtained with 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl fluoride and boron trifluoride etherate (2.0 eq.) as promoter at 0 °C (59%). The deprotection was accomplished stepwise with potassium/sodium hydroxide in acetonitrile/water followed by acid hydrolysis with formic acid resulting in the chemical synthesis of 5′-β-PNG.
- Bachmann, Thomas,Rychlik, Michael
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- Design, synthesis, biological evaluation and molecular docking study of novel pyridoxine-triazoles as anti-Alzheimer's agents
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A series of multi-target natural product-pyridoxine based derivatives were designed, synthesized, characterized and evaluated as anti-Alzheimer agents. In vitro testing revealed the multi-functional properties of compounds such as inhibition of acetylcholinesterase (AChE), antioxidant and metal chelation. Among the series, 5i derivative was found most potent AChE inhibitor, possess antioxidant potential and chelating metal ions. Further binding interaction of 5i with AChE was studied using molecular docking, showed interaction with both PAS and CAS site of AChE. In silico predictions were also performed to predict toxicity and ADME properties of the molecule 5i and found within drug likeness range. Therefore, 5i could be a promising multi-functional compound that can be used for further development of novel drug for Alzheimer disease.
- Bhimaneni, Saipriyanka,Flora, S. J. S.,Pal, Tiyas,Sharma, Abha
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p. 26006 - 26021
(2020/08/21)
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- Production of stereoisomers (by machine translation)
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[Problem] regardless of the scale of the system, various amino compounds can be produced simply and effectively providing its stereoisomers. (1) And (2) a [a] below, the stereoisomers of: (1) H containing asymmetric carbon atom having an amino group-containing substance, formula (I) is reacted with a compound of the, wherein the stereoisomer of substance a; and (2) the formula (I) compound is separated from the stereoisomer. " X and Y may, N or C; R1 - R4 At least one of which is 1, the compound of formula (I) has the ability to separate from its stereoisomers substance group; Y is the time X or N, respectively R4 , R1 There are no; X and Y when the C, R1 And R4 At least one of 1, - NO2 "[Drawing] no (by machine translation)
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Paragraph 0139; 140; 0141; 0142
(2019/05/18)
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- NOVEL PYRIDINE CARBOXYLIC ACID BASED COMPOUND USED AS A P2X1 AND P2X3 RECEPTOR ANTAGONIST, A PRODUCTION METHOD FOR THE SAME AND A COMPOSITION COMPRISING THE SAME
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Provided are a novel pyridine carboxylic acid based compound used as a P2X1 and P2X3 receptor antagonist, a production method for the same and a composition comprising the same. The compound according to the present invention is a powerful antagonist of P2X1 and P2X3 receptors, and hence can be used as a drug for treating or preventing diseases involving neurological pain or chronic inflammatory diseases which are diseases caused by P2X1 and P2X3 receptor activity.
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Paragraph 0116; 0117; 0118
(2013/03/26)
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- Synthesis and structure-activity relationships of carboxylic acid derivatives of pyridoxal as P2X receptor antagonists
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Carboxylic acid derivatives of pyridoxal were developed as potent P2X 1 and P2X3 receptor antagonists with modifications of a lead compound, pyridoxal-5′-phosphate-6-azophenyl-2′,5′- disulfonate (5b, iso-PPADS). The designing strategies included the modifications of aldehyde, phosphate or sulfonate groups of 5b, which may be interacted with lysine residues of the receptor binding pocket, to weak anionic carboxylic acid groups. The corresponding carboxylic acid analogs of pyridoxal-5′- phosphate (1), 13 and 14, showed parallel antagonistic potencies. Also, most of 6-azophenyl derivatives (24-28) of compound 13 or 14 showed potent antagonistic activities similar to that of 5b at human P2X3 receptors with 100 nM range of IC50 values in two-electrode voltage clamp (TEVC) assay system on the Xenopus oocyte. The results indicated that aldehyde and phosphoric or sulfonic acids in 5b could be changed to a carboxylic acid without affecting antagonistic potency at mouse P2X1 and human P2X3 receptors.
- Jung, Kwan-Young,Cho, Joong-Heui,Lee, Jung Sun,Kim, Hyo Jun,Kim, Yong-Chul
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p. 2643 - 2650
(2013/06/27)
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- Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine
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A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3] dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5 μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.
- Pugachev, Mikhail V.,Shtyrlin, Nikita V.,Sysoeva, Lubov P.,Nikitina, Elena V.,Abdullin, Timur I.,Iksanova, Alfiya G.,Ilaeva, Alina A.,Musin, Rashid Z.,Berdnikov, Eugeny A.,Shtyrlin, Yurii G.
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p. 4388 - 4395
(2013/07/27)
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- A new pyridoxal derivative for transamination of N-terminus of proteins
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A new pyridoxal-5-phosphate (PLP) derivative FHMDP was developed for the transamination of different peptides with three most hindered amino acid residues (Leu, Ile, Val) as their N-terminus. Compared to the previously reported reactions of PLP derivatives, the N-terminus transamination could be accomplished efficiently with the new compound.
- Zhang, Meijuan,Zhang, Xuemei,Li, Juan,Guo, Qingxiang,Xiao, Qin
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experimental part
p. 1715 - 1720
(2012/02/03)
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- Polyphosphazenes containing vitamin substituents: Synthesis, characterization, and hydrolytic sensitivity
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Novel polyphosphazenes containing various vitamin substituents were synthesized and characterized, and their sensitivity to hydrolysis and pH behavior was investigated. Vitamins L1, E, and B6 were used because of their biocompatibility, their importance in a variety of biological functions, and their potential to increase the mechanical properties of the resulting polymers, thus making these materials promising candidates for hard tissue engineering scaffolds. Chlorine replacement reactions were carried out initially with the small molecule, hexachlorocyclotriphosphazene, as a model for high polymeric poly(dichlorophosphazene). Because of the steric hindrance generated by vitamin E as a substituent, co-substituted polymers were synthesized with either glycine ethyl ester or sodium ethoxide as the second substituent. Similarly, vitamin B6 was co-substituted with glycine ethyl ester or phenylalanine ethyl ester to favor biodegradability. To prevent cross-linking via multifunctional reagents, the hydroxyl groups in vitamin B6 were protected and subsequently deprotected under acidic conditions after side group linkage to the polymer backbone. The glass transition temperatures of the polymers ranged from -24.0 to 44.0 °C. Hydrolysis of the polymers in deionized water at 37 °C was used as an initial estimate of their hydrolytic sensitivity. Different solid polymers underwent 10-100% weight loss in 6 weeks with the generation of a broad pH range of ~2.5-9. The weight loss during preliminary hydrolysis experiments was attributed to cleavage of the polymer backbone and/or the polymers becoming soluble in the aqueous media during hydrolytic reactions.
- Morozowich, Nicole L.,Weikel, Arlin L.,Nichol, Jessica L.,Chen, Chen,Nair, Lakshmi S.,Laurencin, Cato T.,Allcock, Harry R.
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experimental part
p. 1355 - 1364
(2011/10/09)
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- Characterization of scavengers of γ-ketoaldehydes that do not inhibit prostaglandin biosynthesis
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Expression of cyclooxygenase-2 (COX-2) is associated with the development of many pathologic conditions. The product of COX-2, prostaglandin H2 (PGH2), can spontaneously rearrange to form reactive γ-ketoaldehydes called levuglandins (LGs). This γ-ketoaldehyde structure confers a high degree of reactivity on the LGs, which rapidly form covalent adducts with primary amines of protein residues. Formation of LG adducts of proteins has been demonstrated in pathologic conditions (e.g., increased levels in the hippocampus in Alzheimer's disease) and during physiologic function (platelet activation). On the basis of knowledge that lipid modification of proteins is known to cause their translocation and to alter their function, we hypothesize that modification of proteins by LG could have functional consequences. Testing this hypothesis requires an experimental approach that discriminates between the effects of protein modification by LG and the effects of cyclooxygenase-derived prostanoids acting through their G-protein coupled receptors. To achieve this goal, we have synthesized and evaluated a series of scavengers that react with LG with a potency more than 2 orders of magnitude greater than that with the ε-amine of lysine. A subset of these scavengers are shown to block the formation of LG adducts of proteins in cells without inhibiting the catalytic activity of the cyclooxygenases. Ten of these selective scavengers did not produce cytotoxicity. These results demonstrate that small molecules can scavenge LGs in cells without interfering with the formation of prostaglandins. They also provide a working hypothesis for the development of pharmacologic agents that could be used in experimental animals in vivo to assess the pathophysiological contribution of levuglandins in diseases associated with cyclooxygenase up-regulation.
- Zagol-Ikapitte, Irene,Amarnath, Venkataraman,Bala, Manju,Roberts II, L. Jackson,Oates, John A.,Boutaud, Olivier
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scheme or table
p. 240 - 250
(2011/02/22)
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- Dendrimers in solution can have their remote catalytic groups folded back into the core: Enantioselective transaminations by dendritic enzyme mimics-II
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PAMAM dendrimers with double thioether arms have been synthesized with a pyridoxamine core and terminal chiral amino groups. Transamination to afford natural isomers of phenylalanine and alanine induced enantioselectivity by the peripheral chiral caps, supporting a computer model that indicates folding of dendrimer chains back into the core.
- Wei, Sujun,Wang, Jianing,Venhuizen, Scott,Skouta, Rachid,Breslow, Ronald
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scheme or table
p. 5543 - 5546
(2010/04/30)
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- Process for the preparation of 1,3-Dihydro-6-methylfuro(3,4-c)pyridin-7-ol Derivatives
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The present invention relates to a process for the preparation of 1,3-dihydro-6-methylfuro[3,4-c]pyridin-7-ol derivatives and salts thereof.
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- The synthesis of amino acid pyridoxyl esters
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A multifunctional protective group was suggested on the basis of 4,5-dihydroxymethyl-3-hydroxy-2-methylpyridine (pyridoxine). A preparative method for the synthesis of the starting compounds, pyridoxine ketals, with the use of thionyl chloride was developed, and some new amino acid derivatives, 3,4′-O-isopropylidene-5′-pyridoxyl and 3,4′-O-cyclohexylidene-5′-pyridoxyl esters, were obtained. These resist the action of trifluoroacetic, hydrochloric, hydrobromic, and hydrofluoric acids and can be cleaved by saponification, ammonolysis, hydrazinolysis, hydrogenolysis, or photolysis.
- Sklyarov,Sbitneva,Kopina
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p. 571 - 578
(2007/10/03)
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- Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure-activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamides
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A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compounds 1a [(E)-N-[4 [4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, 4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.
- Nishikawa,Shindo,Ishii,Nakamura,Kon,Uno
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p. 583 - 593
(2007/10/02)
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