- Synthesis and evaluation of a phosphonate analogue of the soluble guanylate cyclase activator YC-1
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Soluble guanylate cyclase (sGC) is activated by the known benzylindazole derivative YC-1 [1-benzyl-3-(5′-hydroxymethyl-2′-furyl)-indazole]. YC-1 also acts synergistically with CO, activating sGC to a level comparable to that achieved upon binding of nitric oxide, the endogenous activator of sGC. We here describe the synthesis of a YC-1 phosphonate analogue with improved aqueous solubility as well as its effects on sGC.
- Martin, Nathaniel I.,Derbyshire, Emily R.,Marletta, Michael A.
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- A novel efficient synthesis of dihydroxyacetone phosphate and bromoacetol phosphate for use in enzymatic aldol syntheses
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Dihydroxyacetone phospate (DHAP,7) and bromoacetol phospate (BAP,6) were synthesized in four and five steps, respectively, starting from 1,3- dibromoacetone (2). The key step involves desymetrization and ketone protection of 2 to prepare alcohol 3. Phosphorylation of 3 followed by hydrogenolysis and then deprotection of the ketal function afforded 6. A solution of 7 was prepared after treatment of 6 with NaOH. This route allows a short and convenient preparation of DHAP in large scale and high purity for application to the synthesis of sugar derivatives and preparation of BAP for triosephosphate isomerase inhibition.
- Gefflaut, Thierry,Lemaire, Marielle,Valentin, Marie-Lise,Bolte, Jean
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- Rapid and flexible synthesis of 1-deoxy-D-xylulose-5-phosphate, the substrate for 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
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1-Deoxy-D-xylulose-5-phosphate (DXP) is a key intermediate in the non-mevalonate pathway to terpenoids in bacteria, and it is the substrate for the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXP-R). In order to study the mechanism of DXP-R, we required a flexible synthesis of the substrate which would allow the incorporation of isotopic labels, and the variation of the two stereocentres. Thus 1,4-dihydroxypent-2-yne was selectively reduced to give the E-olefin, and selective phosphorylation of the primary alcohol followed by oxidation of the secondary alcohol gave a substrate suitable for dihydroxylation. Dihydroxylation using stoichiometric OsO4 in the presence of chiral ligands gave protected DXP in high ee. Final hydrogenolysis gave DXP in quantitative yield and high purity. DXP-R was produced by rapid cloning of the dxr gene from Escherichia coli through controlled expression and ion exchange chromatography. The synthetic DXP was fully active in enzyme assays catalysed by recombinant DXP-R.
- Cox, Russell J,de Andres-Gomez, Ana,Godfrey, Christopher R A
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A one pot synthesis of symmetric methyl, benzyl hydroxy bisphosphonic esters can be obtained, without the use of a dialkylphosphite by introducing a protic reagent which removes the usual α-ketophosphonate step.
- Benech,El Manouni,Leroux
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- The synthesis and aqueous superoxide anion scavenging of water-dispersible lutein esters
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Xanthophyll carotenoids of the C40 series, which includes commercially important compounds such as lutein, zeaxanthin, and astaxanthin, have poor aqueous solubility in the native state. Hawaii Biotech, Inc. (HBI) and others have shown that the aqueous dispersibility of derivatized carotenoids can be increased by varying the chemical structure of the esterified moieties. In the current study, the published series of novel, highly water-dispersible C40 carotenoid derivatives has been extended to include (3R,3′R,6′R)- lutein (β,ε-carotene-3,3′-diol) derivatives. Two novel derivatives were synthesized by esterification with inorganic phosphate and succinic acid, respectively, and subsequently converted to the sodium salts. Red-orange, clear, aqueous suspensions were obtained after addition of these novel derivatives to USP-purified water. Aqueous dispersibility of the disuccinate sodium salt of lutein was 2.85 mg/mL; the diphosphate salt demonstrated a >10-fold increase in dispersibility at 29.27 mg/mL. As reported previously, these aqueous suspensions were obtained without the addition of heat, detergents, co-solvents, or other additives. The direct aqueous superoxide scavenging abilities of these novel derivatives were subsequently evaluated by electron paramagnetic resonance (EPR) spectroscopy in a well-characterized in vitro isolated human neutrophil assay. The novel derivatives were nearly identical aqueous-phase scavengers, demonstrating dose-dependent suppression of the superoxide anion signal (as detected by spin-trap adducts of DEPMPO) in the millimolar range. These lutein-based soft drugs will likely find utility in those commercial and clinical applications for which aqueous-phase singlet oxygen quenching and direct radical scavenging may be required.
- Nadolski, Geoff,Cardounel, Arturo J.,Zweier, Jay L.,Lockwood, Samuel F.
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- Silver-Catalyzed Regioselective Phosphorylation of para-Quinone Methides with P(III)-Nucleophiles
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A simple and efficient method for the silver-catalyzed regioselective phosphorylation of para-quinone methides (p-QMs) with P(III)-nucleophiles (P(OR)3, ArP(OR)2, Ar2P-OR) has been established via Michaelis-Arbuzov-type reaction. A broad range of P(III)-nucleophiles and para-quinone methides are well tolerated under the mild conditions, giving the expected diarylmethyl-substituted organophosphorus compounds with good to excellent yields. Moreover, a series of corresponding enantiomers can be obtained by employing dialkyl arylphosphonite (ArP(OR)2) as substrates. The control experiments and 31P NMR tracking experiments were also performed to gain insights for the plausible reaction mechanism. This protocol may have significant implications for the formation of C(sp3)-P bonds in Michaelis-Arbuzov-type reactions.
- Liu, Yu,Tang, Ke-Wen,Wong, Wai-Yeung,Xie, Jun,Xiong, Biquan,Xu, Shipan,Xu, Weifeng
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p. 14983 - 15003
(2021/11/12)
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- Latent Ruthenium Benzylidene Phosphite Complexes for Visible-Light-Induced Olefin Metathesis
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Herein we report two ruthenium benzylidene complexes with benzylphosphite ligands for olefin metathesis. Unlike the previously reported benzylidene phosphite complexes, the benzylphosphite complexes adopt a cis-dichloro configuration making them latent at ambient temperatures. Irradiation with visible light (420 nm and blue LED) prompts activation of the complexes and induces catalysis of olefin metathesis reactions. One of the complexes, cis-Ru-1, was found to be especially suitable for 3D printing of multilayered polydicyclopentadiene structures with excellent spatial resolutions. Additionally, complex cis-Ru-2 was designed with a chromatic orthogonal "kill switch" based on the 2-nitrobenzyl chemistry, allowing the destruction of the catalyst upon exposure to UV-C light.
- Baranov, Mark,Eivgi, Or,Lemcoff, N. Gabriel,Nechmad, Noy B.,Vaisman, Anna
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p. 2033 - 2038
(2020/02/11)
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- Reagents with a Crystalline Coat
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Tetrakis(dimethoxyphenyl)adamantane (TDA) readily forms crystalline inclusion complexes with reactive, toxic, or malodorous reagents, such as benzoyl chloride, acetyl chloride, cyclohexyl isocyanide, phosphorus trichloride, and trimethylsilyl chloride. The crystals are stable and largely free of the problematic properties of the free reagents. When exposed to solvents such as DMSO or MeOH, the reagents react, and a large portion of the TDA precipitates. The TDA-coated reagents may lead to a safer way of storing, handling, and delivering reagents, and ultimately to synthetic protocols that do not require fume hoods.
- Schwenger, Alexander,Frey, Wolfgang,Richert, Clemens
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supporting information
p. 13706 - 13709
(2016/10/26)
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- INHIBITORS OF DXP SYNTHASE AND METHODS OF USE THEREOF
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Novel inhibitors of DXP synthase and methods of use thereof are disclosed.
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Paragraph 0197; 0198
(2015/09/22)
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- DXP synthase-catalyzed c-n bond formation: Nitroso substrate specificity studies guide selective inhibitor design
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1-Deoxy-D-xylulose 5-phosphate (DXP) synthase catalyzes the first step in the nonmammalian isoprenoid biosynthetic pathway to form DXP from pyruvate and D-glyceraldehyde 3-phosphate (D-GAP) in a thiamin diphosphate-dependent manner. Its unique structure and mechanism distinguish DXP synthase from its homologues and suggest that it should be pursued as an anti-infective drug target. However, few reports describe any development of selective inhibitors of this enzyme. Here, we reveal that DXP synthase catalyzes C-N bond formation and exploit aromatic nitroso substrates as active site probes. Substrate specificity studies reveal a high affinity of DXP synthase for aromatic nitroso substrates compared to the related ThDP-dependent enzyme pyruvate dehydrogenase (PDH). Results from inhibition and mutagenesis studies indicate that nitroso substrates bind to E. coli DXP synthase in a manner distinct from that of D-GAP. Our results suggest that the incorporation of aryl acceptor substrate mimics into unnatural bisubstrate analogues will impart selectivity to DXP synthase inhibitors. As a proof of concept, we show selective inhibition of DXP synthase by benzylacetylphosphonate (BnAP).
- Morris, Francine,Vierling, Ryan,Boucher, Lauren,Bosch, Juergen,Freel Meyers, Caren L.
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p. 1309 - 1315
(2013/08/23)
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- Tailoring the specificity and reactivity of a mechanism-based inactivator of glucocerebrosidase for potential therapeutic applications
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Chaperoning an enzyme: Fluorosugar glycosidase inactivators with tunable phosphorus-based leaving groups react quickly with the catalytic nucleophile in β glucocerebrosidase (blue circle; Bn=benzyl). In Western blot analysis, Gaucher patient cells treated with these inactivators show increased intracellular levels of mutant enzyme, presumably because of increased transit from the endoplasmic reticulum (pale blue) to the lysosome (pale pink). Copyright
- Rempel, Brian P.,Tropak, Michael B.,Mahuran, Don J.,Withers, Stephen G.
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supporting information; experimental part
p. 10381 - 10383
(2011/12/04)
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- Lewis acid or alkyl halide promoted rearrangements of phosphor- and phosphinimidates to N,N-disubstituted phosphor- and phosphinamidates
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In this paper, we describe the synthesis of N,N-disubstituted phosphor- and phosphinamidates via alkyl halide or Lewis acid catalyzed rearrangements of phosphor- or phosphinimidates. Furthermore, we introduce a novel one-pot procedure for the synthesis of N,N-disubstituted phosphoramidates which prevents the isolation of potentially explosive alkyl azide derivatives. In this reaction sequence, several alkyl halides are converted in situ into the corresponding azides and reacted with phosphites to generate phosphorimidates. Final addition of a catalytic amount of Lewis acid to the mixture affords the N,N-disubstituted phosphoramidates in good to excellent overall yields. 1 Introduction 2 Synthesis of N,N-Disubstituted Phosphor- and Phosphinamidates 2.1 Alkyl Halide Catalyzed Rearrangement of Phosphin- and Phosphorimidates 2.2 Lewis Acid Catalyzed Rearrangement of Phosphin- and Phosphorimidates 2.3 One-Pot Procedure for the Formation of N,N-Disubstituted Phosphoramidates from Alkyl Halides 3 Conclusion. Georg Thieme Verlag Stuttgart - New York.
- Wilkening, Ina,Del Signore, Giuseppe,Ahlbrecht, Wiebke,Hackenberger, Christian P. R.
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experimental part
p. 2709 - 2720
(2011/10/18)
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- Methods for synthesis of carotenoids, including analogs, derivatives, and synthetic and biological intermediates
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A method for synthesizing intermediates for use in the synthesis of carotenoid synthetic intermediates, carotenoid analogs, and/or carotenoid derivatives. The carotenoid analog, derivative, or intermediate may be administered to a subject for the inhibition and/or amelioration of any disease that involves production of reactive oxygen species, reactive nitrogen species, radicals and/or non-radicals. In some embodiments, the invention may include methods for synthesizing chemical compounds including an analog or derivative of a carotenoid. Carotenoid analogs or derivatives may include acyclic end groups. In some embodiments, a carotenoid analog or derivative may include at least one substituent. The substituent may enhance the solubility of the carotenoid analog or derivative such that the carotenoid analog or derivative at least partially dissolves in water.
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(2008/12/08)
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- Use of carotenoids and/or carotenoid derivatives/analogs for reduction/inhibition of certain negative effects of COX inhibitors
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Administering carotenoids, and in particular xanthophyll carotenoids, or analogs or derivatives of astaxanthin, lutein, zeaxanthin, lycoxanthin, lycophyll, or lycopene to a subject undergoing treatment with COX-2 inhibitor drugs may reduce at least a portion of the adverse side effects associated with administration of COX-2 selective inhibitor drugs. The carotenoids, or analogs or derivatives thereof may be administered to a subject prior to, at the same time as, or after the commencement of COX-2 selective inhibitor drug therapy. The carotenoids, or analogs or derivatives thereof may be administered to a subject concurrently with COX-2 selective inhibitor drugs therapy. The carotenoids, or analogs or derivatives thereof may be incorporated into pharmaceutical preparation in combination with the COX-2 selective inhibitor drug or may be administered separately. Administration of the analogs or derivatives described herein may reduce peroxidation of LDL and other lipids in the serum and plasma cell membranes of subjects undergoing COX-2 selective inhibitor drug therapy. Administration of the analogs or derivatives described herein may reduce the incidence of deleterious clinical cardiovascular events undergoing COX-2 selective inhibitor drug therapy.
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(2009/01/20)
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- Synthesis of tervalent phosphorus esters in biphasic system using potassium phosphate as unique solid base
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The synthesis of tervalent phosphorus esters continues to be a significant area of interest, much of it again directed toward the synthesis of phosphite ligands for metal-catalyzed reactions. Typically, they were obtained through esterification of the corresponding phosphorus chlorides with the appropriate alcohols in the presence of an amine. In this paper, we present a new method for the synthesis of tervalent phosphorus esters, not yet mentioned in the literature, when potassium phosphate, as a unique base, is used in liquid-solid system. Symmetrical and unsymmetrical phosphites were obtained with good yields (65%-80%) using this method. The compounds were characterized by 31P NMR spectroscopy.
- Ilia, Gheorghe,Iliescu, Smaranda,Macarie, Lavinia,Popa, Adriana
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p. 360 - 364
(2008/09/20)
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- New blood coagulation factor inhibitors
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The invention relates to novel compounds with formula (I) wherein R1-R7 are as herein defined useful as blood coagulation factor inhibitors. The compounds (I) may be used for treatment of thrombotic conditions or as stabilizers of liquid formulations of blood coagulation factors, in particular liquid formulations of FVIIA, Factor VII variants, or Factor VII derivatives.
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(2008/12/08)
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- STRUCTURAL CAROTENOID ANALOGS OR DERIVATIVES FOR THE MODULATION OF SYSTEMIC AND/OR TARGET ORGAN REDOX STATUS
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Methods for the reduction or prevention of oxidative stress in a human subject comprising administering to the human subject an effective amount of a composition comprising xanthophyll carotenoids, or analogs or derivatives of astaxanthin, lutein, zeaxanthin, lycoxanthin, lycophyll, or lycopene are described. Also described are compositions comprising xanthophyll carotenoids, or analogs or derivatives of astaxanthin, lutein, zeaxanthin, lycoxanthin, lycophyll, or lycopene, the compositions being effective for the reduction or prevention of oxidative stress in a human subject, especially cardiac oxidative stress.
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(2010/11/27)
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- The chemical mechanism of D-1-deoxyxylulose-5-phosphate reductoisomerase from Escherichia coli
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(Chemical Equation Presented) Find the way: 3-[2H]- and 4-[ 2H]-labeled 1-deoxyxylulose-5-phosphate were synthesized and used to investigate the chemical mechanism of 1-deoxyxylulose-5-phosphate reductoisomerase (DXR) from E. coli. The observation of inverse secondary kinetic isotope effects for both labeled substrates indicates that DXR uses a retro-aldol/aldol mechanism in which the recombination reaction is the rate-limiting step (see scheme).
- Wong, Ursula,Cox, Russell J.
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p. 4926 - 4929
(2008/02/10)
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- WATER-DISPERSIBLE CAROTENOIDS, INCLUDING ANALOGS AND DERIVATIVES
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A chemical composition; comprising one or more carotenoid analogs or derivatives having a structure (I), (II) and (III) where each R3 is independently hydrogen or methyl, and where each R1 and R2 are independently wherein each R5 is independently hydrogen, -OH, or -OR6, wherein at least one R5 group is -OR6; wherein each R6 is independently: alkyl; aryl; -alkyl-N(R7)2; -aryl-N(R7)2; -alkyl-N+ (R7)3; -aryl-N+(R7)3; -alkyl-CO2R7; -aryl-CO2R7; -alkyl-CO2; -aryl-CO2; -CO2R8; -P(O)(OR8)2; -S(O)(OR8)2; an amino acid; a peptide, a carbohydrate; -C(O)- (CH2)0-CO2R9; a nucleoside residue, or a co-antioxidant; wherein R7 is hydrogen, alkyl, or aryl; wherein R8 is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; wherein R9 is hydrogen; alkyl; aryl; -P(0)(OR8)2; -S(0)(OR8)2; an amino acid; a peptide, a carbohydrate; a nucleoside, or a co-antioxidant; and wherein n is 1 to 9. The compounds are useful for the inhibition and amelioration of diseases resulting in change and/or loss of vision.
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(2008/06/13)
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- Reduction in complement activation and inflammation during tissue injury by carotenoids, carotenoid analogs, or derivatives thereof
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Administering water-soluble or dispersible synthetic analogs or derivatives of astaxanthin, lutein, zeaxanthin, or lycophyll and/or other carotenoids to a subject may reduce some of the adverse effects of inflammation in a body organ or tissue. The analogs or derivatives may be incorporated into pharmaceutical, over-the-counter, or nutraceutical preparations. Administration of the analogs or derivatives described herein may reduce deposition of inflammatory mediators such as C-reactive protein, complement system proteins or the membrane attack complex (MAC) in tissues. Reduced deposition of these molecules in tissues may reduce cell damage and/or lysis in the tissues.
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(2008/06/13)
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- CAROTENOIDS, CAROTENOID ANALOGS, OR CAROTENOID DERIVATIVES FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
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A method and system used for treating proliferative disorders using carotenoids, carotenoid analogs, and/or carotenoid derivatives. The method and system may be used for chemoprevention and/or chemotherapy. The method and system may induce apoptosis in target cells, tissues, and/or organs. The analog, derivative, or intermediate may be administered to a cell, a group of cells, a tissue, an organ or a subject, such that at least a portion of the undesirable consequences of the proliferative disorder are thereby reduced.
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(2008/06/13)
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- METHODS FOR SYNTHESIS OF CHIRAL INTERMEDIATES OF CAROTENOIDS, CAROTENOID ANALOGS, AND CAROTENOID DERIVATIVES
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A method used for synthesizing intermediates for use in the synthesis of carotenoids and carotenoid analogs, and/or carotenoid derivatives. In some embodiments, the invention includes methods for synthesizing optically active intermediates useful for the synthesis of optically active carotenoids.
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Page/Page column 57
(2010/10/20)
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- Carotenoids, carotenoid analogs, or carotenoid derivatives for the treatment of visual disabilities
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A method and system used for treating visual disabilities using carotenoids, carotenoid analogs, and/or carotenoid derivatives. The analog, derivative, or intermediate may be administered such that a subject's risk of experiencing diseases associated with visual disabilities may be thereby reduced. Analogs or derivatives of carotenoids may include substituents including for example co-antioxidants (e.g., Vitamin C and Vitamin C analogs). The carotenoid analog or derivative may be synthetic. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include an acyclic alkene including at least one substituent and/or a cyclic ring including at least one substituent. In some embodiments, a carotenoid analog or derivative may include at least one substituent. The substituent may enhance the solubility of the carotenoid analog or derivative such that the carotenoid analog or derivative at least partially dissolves in water.
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(2010/11/24)
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- CAROTENOID ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF INFLAMMATION
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A method for inhibiting and/or ameliorating the occurrence of diseases in a human subject whereby a subject is administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative. In some embodiments, the administration of analogs or derivatives of carotenoids may inhibit and/or ameliorate the occurrence of diseases in subjects. In some embodiments, analogs or derivatives of carotenoids may be water-soluble and/or water dispersible. Maladies that may be treated with analogs or derivatives of carotenoids embodied herein may include diseases that provoke or trigger an inflammatory response. In an embodiment, asthma may be treated with analogs or derivatives of carotenoids embodied herein. In an embodiment, administering analogs or derivatives of carotenoids embodied herein to a subject may control or affect the bioavailability of eicosanoids. In an embodiment, atherosclerosis may be treated with analogs or derivatives of carotenoids embodied herein. In an embodiment, administering the analogs or derivatives of carotenoids embodied herein to a subject may control or affect the bioavailability of 5-LO-catalyzed eicosanoid metabolites. In an embodiment, 5-LO-catalyzed eicosanoid metabolites that may be controlled or affected by administering analogs or derivatives of carotenoids to a subject may include proinflammatory effector molecules (e.g., leukotrienes).
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(2010/02/14)
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- p-substituted benzyl hydroxybisphosphonates: Synthesis and hydrolysis
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Several hydroxybisphosphonate benzyl esters have been synthesized for study. The effect of the benzyl substituent on the acidic hydrolysis of the phosphonic esters has also been studied.
- Mallard, Isabelle,Benech, Jean-Marc,Lecouvey, Marc,Leroux, Yves
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- Synthesis of New α-Ketophosphonates
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Using the Arbuzov reaction, asymmetrical or symmetrical benzyl α-ketophosphonates can be synthesized.In the case of symmetrical benzyl α-ketophosphonates, it was observed that the modification of benzyl groups influences the yield of the Arbuzov reaction. - Keywords: α-ketophosphonate; benzyl groups; Arbuzov reaction
- Benech, Jm.,Coindet, M.,Manouni, D. El,Leroux, Y.
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p. 377 - 384
(2007/10/03)
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- First Use of Benzyl Phosphites in the Michaelis-Arbuzov Reaction Synthesis of Mono-, Di-, and Triphosphate Analogs
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Benzyl phosphites were used in the Michaelis-Arbuzov reaction.Special experimental conditions allowed preparation of a set of phosphonate analogs of mono-, di-, and triphosphate.Furthermore, regioselective mono-deprotection mades these molecules useful building blocks for the synthesis of analogs of polyphosphorylated compounds of biological interest (e.g. nucleotides), after removal of all phosphonate benzyl ester groups under very mild conditions and high yields.
- Saady, Mourad,Lebeau, Luc,Mioskowski, Charles
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p. 670 - 678
(2007/10/02)
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- AMINOPHOSPHONIC ACID AND AMINOPHOSPHINIC ACID ANALOGUES OF ASPARTIC ACID
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4-Oxoazetidin-2-ylphosphonates and phosphinates, obtained from Arbusov reactions of 4-acetoxyazetidin-2-one and 4α-acetoxy-3β-phthalimido-2-one with a variety of phosphites and phosphonites, were hydrolysed to β-phosphono- and β-phosphino β-alanine (phosphono- and phosphinoaspartic acid) derivatives.In model studies for their incorporation in peptides, conditions for the selective removal of protecting groups for carboxylic acids, phosphonic and phosphinic acids, and amines, in derived di- and tripeptides were investigated.Alanyl and alanyl alanyl peptide incorporation into bacteria was studied.
- Campbell, Malcolm M.,Carruthers, Nicholas I.,Mickel, Stuart J.
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p. 2513 - 2524
(2007/10/02)
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- Selective formation of ethanol from methanol, hydrogen and carbon monoxide
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A process for the selective formation of ethanol which comprises contacting methanol, hydrogen and carbon monoxide with a catalyst system comprising cobalt acetylacetonate, a tertiary organo Group V A compound of the periodic Table, a first promoter comprising an iodine compound and a second promoter comprising a ruthenium compound.
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