- Unsaturated α-aminopimelic acids as potent inhibitors of meso-diaminopimelic acid (DAP) D-dehydrogenase
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Two nonproteinogenic amino acids 5 and 6 have been efficiently prepared using an S(H)2' allylstannane coupling reaction and a Wittig reaction, respectively, to effect the key steps; kinetic studies show these compounds to be reversible inhibitors of DAP dehydrogenase with K(i) values of 5.3 (competitive) and 44 μM (noncompetitive), respectively.
- Sutherland, Andrew,Caplan, Jennifer F.,Vederas, John C.
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Read Online
- Synthesis of Imidazole and Histidine-Derived Cross-Linkers as Analogues of GOLD and Desmosine
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Amino acid derivatives with a central cationic heterocyclic core (e.g., imidazolium) are biologically relevant cross-linkers of proteins and advanced glycation end (AGE) products. Here, imidazolium-containing cross-linkers were synthesized from imidazole or histidine by N-alkylation employing aspartate- and glutamate-derived mesylates as key step. Biological investigations were carried out to probe the biocompatibility of these compounds.
- Sch?del, Nicole,Icik, Esra,Martini, Maike,Altevogt, Luca,Ramming, Isabell,Greulich, Andreas,Baro, Angelika,Bilitewski, Ursula,Laschat, Sabine
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supporting information
p. 2260 - 2268
(2021/03/04)
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- Structure-Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer
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Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure-activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogues missing the nonchlorinated methyl groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogues with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the methyl ether on the tetramic acid fragment are essential for activity. The SAR optimized analogue 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.
- Yan, Luping,Banuelos, Carmen A.,Mawji, Nasrin R.,Patrick, Brian O.,Sadar, Marianne D.,Andersen, Raymond J.
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p. 797 - 813
(2020/11/13)
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- Zelkovamycin is an OXPHOS Inhibitory Member of the Argyrin Natural Product Family
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Natural products (NPs) are an important inspirational source for developing drugs and chemical probes. In 1999, the group of ōmura reported the constitutional elucidation of zelkovamycin. Although largely unrecognized so far, this NP displays structural s
- Krahn, Daniel,Heilmann, Geronimo,Vogel, Felix C. E.,Papadopoulos, Chrisovalantis,Zweerink, Susanne,Kaschani, Farnusch,Meyer, Hemmo,Roesch, Alexander,Kaiser, Markus
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supporting information
p. 8524 - 8531
(2020/07/02)
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- Selenolysine: A New Tool for Traceless Isopeptide Bond Formation
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Despite their biological importance, post-translationally modified proteins are notoriously difficult to produce in a homogeneous fashion by using conventional expression systems. Chemical protein synthesis or semisynthesis offers a solution to this problem; however, traditional strategies often rely on sulfur-based chemistry that is incompatible with the presence of any cysteine residues in the target protein. To overcome these limitations, we present the design and synthesis of γ-selenolysine, a selenol-containing form of the commonly modified proteinogenic amino acid, lysine. The utility of γ-selenolysine is demonstrated with the traceless ligation of the small ubiquitin-like modifier protein, SUMO-1, to a peptide segment of human glucokinase. The resulting polypeptide is poised for native chemical ligation and chemoselective deselenization in the presence of unprotected cysteine residues. Selenolysine's straightforward synthesis and incorporation into synthetic peptides marks it as a universal handle for conjugating any ubiquitin-like modifying protein to its target.
- Dardashti, Rebecca Notis,Kumar, Shailesh,Sternisha, Shawn M.,Reddy, Post Sai,Miller, Brian G.,Metanis, Norman
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supporting information
p. 4952 - 4957
(2020/04/07)
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- Synthesis and Biological Evaluation of a Library of AGE-Related Amino Acid Triazole Crosslinkers
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Three N-Boc-protected amino acids, l-serine, l-aspartic, and l-glutamic acid, were either converted into their methyl azidoalkanoates or various alkynes via Bestmann-Ohira strategy or via reaction with propargylamine and propargyl bromide, respectively. The Cu-catalyzed click reaction provided a library of amino acid based triazoles, which were further N-methylated to triazolium iodides or deprotected and precipitated as free amino acid triazole dihydrochlorides. The biological properties of all derivatives were investigated by cytotoxicity assay (against L929 mouse fibroblasts) and broth microdilution method (E. coli ΔTolC and S. aureus). First results reveal complete inactivity for triazolium iodides with cell viabilities and microbial growths nearly 100 %, indicating them as possible analogs of advanced glycation endproducts (AGEs).
- Agelidis, Nektarios,Altevogt, Luca,Baro, Angelika,Bilitewski, Ursula,Bugdayci, Bakiye,Icik, Esra,Jolly, Anthony,L?ffler, Paul,Laschat, Sabine
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supporting information
(2020/09/01)
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- HERBICIDAL COMPOSITIONS
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The present invention relates herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations of the invention comprise at least one pyridazine derivative of Formula (I) as defined herein, in combination with at least one further herbicide that is a pyrrolidinone derivatives of the Formula (II) as defined herein.
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Page/Page column 61-62
(2020/08/28)
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- HERBICIDAL COMPOSITIONS
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The present invention relates novel herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations of the invention comprise at least one pyridazine derivative as defined herein, in combination with at least one futher herbicide that is an acetoclactase synthase (ALS) inhibitor.
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Page/Page column 57-58
(2020/08/28)
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- HERBICIDAL COMPOSITIONS
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The present invention relates to novel herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations of the invention comprise at least one pyridazine derivative of Formula (I), in combination with at least one futher herbicide that is a non-selective herbicide, a herbicide that acts through the inhibition of protoporphoryinogen oxidase, or a herbicide that inhibits photosystem II in photosynthesis.
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Page/Page column 65; 66
(2020/08/28)
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- HERBICIDAL COMPOSITIONS
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The present invention relates to herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations comprising at least one pyridazine derivative of Formula (I) as defined herein, in combination with at least one further herbicide that is a compound of Formula (II) as defined herein.
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Page/Page column 55
(2020/08/28)
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- PRE-HARVEST DESICCATION METHOD
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A method for the pre-harvest desiccation of crop plants which comprises applying to the crop plants an effective amount of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, wherein the substituents are as defined in claim 1.
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Page/Page column 92
(2020/08/28)
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- HERBICIDAL COMPOSITIONS
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The present invention relates novel herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations of the invention comprise at least one pyridazine derivative of Formula (I), in combination with at least one futher herbicide that is a HPPD-inhibitor herbicide, a synthetic AUXIN herbicide, a herbicide that acts through the inhibition of ACCase, or a herbicide that inhibits cell division through interference with VLCFA biosynthesis.
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Page/Page column 65
(2020/08/28)
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- HERBICIDAL COMPOUNDS
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Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially as herbicides.
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Page/Page column 98; 99
(2019/03/05)
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- Synthesis of 5-Cyano-Tryptophan as a Two-Dimensional Infrared Spectroscopic Reporter of Structure
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A concise synthesis of protected 5-cyano-l-tryptophan (Trp5CN) has been developed for 2D IR spectroscopic investigations within either peptides or proteins. To assess the potential of differently substituted cyano-tryptophans, several model cya
- Chalyavi, Farzaneh,Gilmartin, Philip H.,Schmitz, Andrew J.,Fennie, Michael W.,Tucker, Matthew J.
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supporting information
p. 7528 - 7532
(2018/06/04)
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- Two Distinct Mechanisms for C-C Desaturation by Iron(II)- and 2-(Oxo)glutarate-Dependent Oxygenases: Importance of α-Heteroatom Assistance
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Hydroxylation of aliphatic carbons by nonheme Fe(IV)-oxo (ferryl) complexes proceeds by hydrogen-atom (H?) transfer (HAT) to the ferryl and subsequent coupling between the carbon radical and Fe(III)-coordinated oxygen (termed rebound). Enzymes that use H?-abstracting ferryl complexes for other transformations must either suppress rebound or further process hydroxylated intermediates. For olefin-installing C-C desaturations, it has been proposed that a second HAT to the Fe(III)-OH complex from the carbon α to the radical preempts rebound. Deuterium (2H) at the second site should slow this step, potentially making rebound competitive. Desaturations mediated by two related l-arginine-modifying iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases behave oppositely in this key test, implicating different mechanisms. NapI, the l-Arg 4,5-desaturase from the naphthyridinomycin biosynthetic pathway, abstracts H? first from C5 but hydroxylates this site (leading to guanidine release) to the same modest extent whether C4 harbors 1H or 2H. By contrast, an unexpected 3,4-desaturation of l-homoarginine (l-hArg) by VioC, the l-Arg 3-hydroxylase from the viomycin biosynthetic pathway, is markedly disfavored relative to C4 hydroxylation when C3 (the second hydrogen donor) harbors 2H. Anchimeric assistance by N6 permits removal of the C4-H as a proton in the NapI reaction, but, with no such assistance possible in the VioC desaturation, a second HAT step (from C3) is required. The close proximity (≤3.5 ?) of both l-hArg carbons to the oxygen ligand in an X-ray crystal structure of VioC harboring a vanadium-based ferryl mimic supports and rationalizes the sequential-HAT mechanism. The results suggest that, although the sequential-HAT mechanism is feasible, its geometric requirements may make competing hydroxylation unavoidable, thus explaining the presence of α-heteroatoms in nearly all native substrates for Fe/2OG desaturases.
- Dunham, Noah P.,Chang, Wei-Chen,Mitchell, Andrew J.,Martinie, Ryan J.,Zhang, Bo,Bergman, Jonathan A.,Rajakovich, Lauren J.,Wang, Bo,Silakov, Alexey,Krebs, Carsten,Boal, Amie K.,Bollinger, J. Martin
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supporting information
p. 7116 - 7126
(2018/05/15)
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- TOTAL SYNTHESIS OF THAXTOMIN A ANALOGUES AND THEIR INTERMEDIATES
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Improved synthetic methods for the production of thaxtomin analogues, particularly thaxtomin A, and intermediates therefore such as substituted tryptophans and in particular, 4-nitro-L-tryptophan, and substituted phenyl acrylic acids are disclosed. Bioass
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Paragraph 0030; 0031
(2014/09/30)
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- Synthesis of cis -5-trifluoromethylproline from l -glutamic acid
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The diastereoselective synthesis of cis-5-trifluoromethylproline (5-Tfm-Pro) from l-glutamic acid is described. 5-Tfm-Pro could be obtained through a seven-step linear sequence. Trifluoromethylation of the glutamic-derived ester or aldehyde and subsequent reduction of the cyclic imine are the key steps in the synthesis. Georg Thieme Verlag Stuttgart New York.
- Ortial, Stéphanie,Dave, Rajesh,Benfodda, Zohra,Bénimélis, David,Meffre, Patrick
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supporting information
p. 569 - 573
(2014/03/21)
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- Total synthesis of chloptosin: A dimeric cyclohexapeptide
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Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme. Copyright
- Oelke, Alexander J.,Antonietti, Francesca,Bertone, Leonardo,Cranwell, Philippa B.,France, David J.,Goss, Rebecca J. M.,Hofmann, Tatjana,Knauer, Stephan,Moss, Steven J.,Skelton, Paul C.,Turner, Richard M.,Wuitschik, Georg,Ley, Steven V.
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scheme or table
p. 4183 - 4194
(2011/06/17)
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- Total synthesis of argyrins A and e
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The total synthesis of argyrins A and E were accomplished using a convergent strategy by condensation of one tripeptide and two dipeptide fragments. The synthesis strategy, which was developed for the protection of peptide fragments and identification of the optimum macrocylization site, can be applied to further synthetic studies involving other members of the argyrin family.
- Wu, Wenbin,Li, Zheng,Zhou, Guangbiao,Jiang, Sheng
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supporting information; experimental part
p. 2488 - 2491
(2011/05/09)
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- Synthesis of 2-amino-5-hydroxycaprolactam derivatives mediated by E-selective olefination and asymmetric oxidation of the enol ether
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The asymmetric synthesis of 2-amino-5-hydroxycaprolactam derivatives is essential for exploring the antitumor properties of ester-bearing bengamides. In this study, chiral caprolactam isomers were achieved on the basis of highly E-selective Wittig olefina
- Li, Hong,Liu, Yingxue,Liu, Qijun,Hu, Wenhui,Zhou, Guo-Chun
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body text
p. 4068 - 4074
(2011/02/25)
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- Thiyl glycosylate of olefinic proteins: S-linked glycoconjugate synthesis
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Tagged for thiolation: A novel glycoconjugation strategy utilizes a non-natural olefin-containing amino acid (homoallylglycine, Hag) as a "tag" for modification and a photoinitiated hydroglycothiolation reaction that is selective only for the Hag olefinic "tag". Application of this method to a number of model proteins allowed complete and precise site-selective glycosylate generating glycoconjugates that include, for example, virus-like particles displaying up to 180 glycans at preselected positions (see scheme).
- Floyd, Nicola,Vijayakrishnan, Balakumar,Koeppe, Julia R.,Davis, Benjamin G.
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supporting information; experimental part
p. 7798 - 7802
(2010/04/05)
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- Synthetic studies on (-)-lemonomycin: An efficient asymmetric synthesis of lemonomycinone amide
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Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert- butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo's phase transfer catalyst [O-(9)-ally-N-(9-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after chemoselective hydrolysis of the imine function (THF/H2O/AcOH), the substituted L-tert-butyl phenylalanate 13 in 85% yield. A Pictet-Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cisdisubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22, which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to α-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26 afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)2, H2, MeOH, 0°C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H2O), and oxidation of hydroquinone to quinone [(NH4)2Ce(NO 3)6, H2O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps
- Wu, Yan-Chao,Bernadat, Guillaume,Masson, Geraldine,Couturier, Cedric,Schlama, Thierry,Zhu, Jieping
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supporting information; experimental part
p. 2046 - 2052
(2009/08/07)
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- A practical method for selective cleavage of a tert-butoxycarbamoyl N-protective group from N,N-diprotected α-amino acid derivatives using montmorillonite K-10
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A new, practical, and mild procedure for the selective cleavage of a tert-butoxycarbonyl group (Boc) in N-Boc-N-acyl-diprotected amines is described. When applied to α-amino acids, complete integrity of the stereochemistry was observed. The use of N,N-di-Boc-α-amino-δ- and γ-hydroxy esters provided both δ- and γ-lactones in very good yields. The method is based on the use of Montmorillonite K-10 either in CH 2Cl2 at room temperature or in toluene at 65°C and is compatible with the presence of a large range of functional and other protecting groups in the substrates. In most cases virtually pure samples are obtained after filtration and removal of solvents. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Hernandez, J. Nicolas,Crisostomo, Fernando R. Pinacho,Martin, Tomas,Martin, Victor S.
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p. 5050 - 5058
(2008/03/18)
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- COMBINATION THERAPY WITH INHIBITORS OF INDUCIBLE NITRIC OXIDE SYNTHASE AND ALKYLATING AGENTS
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A combination therapy comprising administration of a carbamoylating chemotherapeutic agent in conjunction with administration of a selective iNOS inhibitor compound is disclosed. Optionally, resection and radiation therapy are provided with the therapeutic combination. A medicament comprising a carbamoylating chemotherapeutic agent and a selective iNOS inhibitor compound together with a pharmaceutically acceptable carrier is further disclosed. A kit comprising a carbamoylating chemotherapeutic agent and a selective iNOS inhibitor compound is further disclosed.
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Page/Page column 100-101
(2010/02/11)
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- METHODS FOR TREATMENT AND PREVENTION OF GASTROINTESTINAL CONDITIONS
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Therapeutic methods for the prevention ad treatment of conditions and diseases of the gastrointestinal tract involving an overproduction of nitric oxide by inducible nitric oxide synthase are described, the methods including administering to a subject in need thereof a therapeutically effective amount of a selective inhibitor of inducible nitric oxide synthase (iNOS). The methods also include the use of selective inhibitors of iNOs in combination with other therapeutic agents, including antimicrobial agents and antisecretory agents.
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Page/Page column 50
(2010/02/06)
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- Convenient syntheses of (3S,5S)-carbapenam-3-carboxylates and their biosynthetic relevance
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Starting from readily available glutamate derivatives, facile stereoselective syntheses of (3S,5S)-carbapenam-3-carboxylates have been developed. Their significance in confirming the absolute configuration of the natural material is discussed.
- Bycroft, Barrie W.,Chhabra, Siri Ram,Kellam, Barrie,Smith, Paul
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p. 973 - 976
(2007/10/03)
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- A facile two-step synthesis of novel ring-A double substituted tryptophan building blocks for combinatorial chemistry
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A fast synthesis of ring-A disubstituted Fmoc and Boc protected L-tryptophan analogs was achieved starting from the appropriate 2,4- or 2,3-disubstituted phenylhydrazines and optically active N,N-diprotected L-glutamic acid γ-aldehydes, utilizing a Fischer-indole synthesis as a key step. Unlike most of the previously reported methods, that required the multistep stereoselective generation of a chiral carbon, this fast methodology is useful for generating optically active ring-A disubstituted protected tryptophans starting from a simple and common chiral precursor. These building blocks have a wide application scope in peptide and combinatorial chemistry fields.
- Gorohovsky, Sofia,Meir, Simcha,Shkoulev, Vladimir,Byk, Gerardo,Gellerman, Garry
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p. 1411 - 1414
(2007/10/03)
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- Enantiospecific synthesis of α-amino acid semialdehydes: A key step for the synthesis of unnatural unsaturated and saturated α-amino acids
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The enantiospecific synthesis of unnatural unsaturated and saturated α- amino acids based on a Wittig type reaction is described. The versatile synthetic intermediates, L-glutamic and L-aspartic acid semialdehydes, are obtained from the corresponding N,N-di-Boc-diesters, by the selective reduction of the ω-ester with DIBAL under controlled conditions. The semialdehydes are chemically stable for a prolonged time and react with various phosphorous ylides, under controlled conditions, to produce the enantiomerically pure unsaturated α-amino acids in high yields. The method is equally applicable to homologated diesters obtained by the presented methodology providing unsaturated amino acids with variable unsaturated- positions and geometries. The corresponding saturated products can be obtained by simple hydrogenation.
- Padron, Jose M.,Kokotos, George,Martin, Tomas,Markidis, Theodoros,Gibbons, William A.,Martin, Victor S.
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p. 3381 - 3394
(2007/10/03)
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