- Synthesis and Stability of the Cyclic Sulfamidate of N-Trityl-L-Serine Methyl Ester
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The title compound 12, prepared in three steps from L-serine methyl ester, is thermally stable 50 deg C; the formation of the cyclic sulfamidite 9, rather than acyclic products, in the reaction of thionyl chloride with vic-amino alcohol 7 is far more de
- Pilkington, Melanie,Wallis, John D.
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Read Online
- Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1, and MBJ-0035
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The madurastatins are pentapeptide siderophores originally described as containing an unusual salicylate-capped N-terminal aziridine ring. Isolation of madurastatin C1 (1) (also designated MBJ-0034), from Actinomadura sp. DEM31376 (itself isolated from a
- Tyler, Andrew R.,Mosaei, Hamed,Morton, Stephanie,Waddell, Paul G.,Wills, Corinne,McFarlane, William,Gray, Joe,Goodfellow, Michael,Errington, Jeff,Allenby, Nick,Zenkin, Nikolay,Hall, Michael J.
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Read Online
- Straightforward synthesis and antioxidant studies of chalcogenoaziridines
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Herein we reported the synthesis of chalcogenoaziridines through the introduction of the organoselenium moiety in the aziridine framework through the nucleophilic substitution of the OTs leaving group. In addition, the antioxidant activity, as reflected b
- Borges, Rodrigo,Andrade, Floyd C.D.,Schwab, Ricardo S.,Sousa, Fernanda S.S.,de Souza, Maurice Neto,Savegnago, Lucielli,Schneider, Paulo H.
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supporting information
p. 3501 - 3504
(2016/07/15)
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- Total synthesis and activity of the metallo-β-lactamase inhibitor aspergillomarasmine A
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Resistance to β-lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal-dependent activation of a water molecule. Serine β-lactamases are countered in the c
- Koteva, Kalinka,King, Andrew M.,Capretta, Alfredo,Wright, Gerard D.
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supporting information
p. 2210 - 2212
(2016/02/19)
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- NOVEL COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (formula 1) wherein R1,R2, R3, R4, R5, X, m and n are defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.
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Page/Page column 101-102
(2016/02/26)
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- KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE
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Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.
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Paragraph 0571; 0572
(2016/09/26)
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- Studies on the synthesis of orthogonally protected azalanthionines, and of routes towards β-methyl azalanthionines, by ring opening of N-activated aziridine-2-carboxylates
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Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para- methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding β-methyl azalanthionines have, so far, been unsuccessful.
- O'Brien, Keith,ó Proinsias, Keith,Kelleher, Fintan
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supporting information
p. 5082 - 5092
(2014/07/08)
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- Studies on the synthesis of orthogonally protected azalanthionines, and of routes towards β-methyl azalanthionines, by ring opening of N-activated aziridine-2-carboxylates
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Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para-methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding β-methyl azalanthionines have, so far, been unsuccessful.
- O'Brien, Keith,ó Proinsias, Keith,Kelleher, Fintan
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p. 5082 - 5092
(2014/12/10)
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- Synthesis of 1,2- trans -2-Acetamido-2-deoxyhomoiminosugars
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The first synthesis of 1,2-trans-homoiminosugars devised as mimics of I-d-GlcNAc and I-d-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic sulfite and a I-amino alcohol skeletal rearrangement applied to a polyhydroxylated azep
- Blriot, Yves,Tran, Anh Tuan,Prencipe, Giuseppe,Jagadeesh, Yerri,Auberger, Nicolas,Zhu, Sha,Gauthier, Charles,Zhang, Yongmin,Dsir, Jrme,Adachi, Isao,Kato, Atsushi,Sollogoub, Matthieu
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supporting information
p. 5516 - 5519
(2015/02/19)
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- Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group
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We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing "affinity bait" (AB) and "chemical reporter" (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents' utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.
- Park, Ki Duk,Stables, James P.,Liu, Rihe,Kohn, Harold
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scheme or table
p. 2803 - 2813
(2010/08/21)
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- Lacosamide isothiocyanate-based agents: Novel agents to target and identify lacosamide receptors
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(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults.Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy) propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2. 2009 American Chemical Society.
- Ki, Duk Park,Morieux, Pierre,Salomé, Christophe,Cotten, Steven W.,Reamtong, Onrapak,Eyers, Claire,Gaskell, Simon J.,Stables, James P.,Liu, Rihe,Kohn, Harold
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supporting information; experimental part
p. 6897 - 6911
(2010/04/24)
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- Asymmetrie total syntheses of (-)-renieramycin M and G and (-)-jorumycin using aziridine as a lynchpin
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"Chemical Equation Presented" By exploring the triple reactivity of two aziridines and double nucleophilicity of two aromatics, convergent and versatile syntheses of the above four natural products were developed.
- Wu, Yan-Chao,Zhu, Jieping
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supporting information; experimental part
p. 5558 - 5561
(2010/02/28)
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- NOVEL N-BENZYLAMIDE SUBSTITUTED DERIVATIVES OF 2-(ACYLAMIDO)ACETIC ACID AND 2-(ACYLAMIDO)PROPIONIC ACIDS: POTENT NEUROLOGICAL AGENTS
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A first aspect of the invention is a compound (sometimes also referred to herein as an "active agent" or "active compound") of Formula (I) or ( Ia): or a pharmaceutically acceptable salt or prodrug thereof. Compositions thereof and methods of using the same (e.g. for the treatment of a neurological disease) are also described.
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Page/Page column 28
(2009/12/27)
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- The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1
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A thiodipeptide carrier system is shown to be effective at enabling a range of covalently bound molecules, including benzyl, benzoyl and ibuprofen conjugates, to be transported via the intestinal peptide transporter PepT1, demonstrating its potential as a rational drug delivery target.
- Foley, David,Pieri, Myrtani,Pettecrew, Rachel,Price, Richard,Miles, Stephen,Lam, Ho Kam,Bailey, Patrick,Meredith, David
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supporting information; experimental part
p. 3652 - 3656
(2009/10/23)
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- An enantiospecific approach to triazolylalanine derivatives
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An efficient and practical route to an enantiomerically pure aziridinylmethyl azide is described that can be transformed to the corresponding triazole by a copper-catalysed [3+2] alkyne cycloaddition reaction. The transformation of these intermediates int
- Jamookeeah, Clare E.,Beadle, Christopher D.,Harrity, Joseph P. A.
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scheme or table
p. 133 - 137
(2009/06/18)
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- Stereoselective syntheses of 4-oxa diaminopimelic acid and its protected derivatives via aziridine ring opening
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Regio- and stereoselective aziridine ring opening with oxygen nucleophiles derived from serine and threonine provides a route to stereochemically pure 4-oxa-2,6-diaminopimelic acid (oxa-DAP) and its methyl-substituted derivatives. Oxa-DAP is a substrate of DAP epimerase, a key enzyme for biosynthesis of L-lysine and formation of peptidoglycan precursors. Orthogonally protected analogues of lanthionine and/β-methyllanthionine wherein oxygen replaces sulfur were prepared that could be used for solid-supported peptide synthesis to make oxa derivatives of lantibiotics.
- Liu, Hongqiang,Pattabiraman, Vijaya R.,Vederas, John C.
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p. 4211 - 4214
(2008/03/13)
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- Novel polymer-bound aminoalcohol ligands for the asymmetric addition of diethylzinc to aldehydes
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The synthesis of several novel polymer-supported aziridine-containing aminoalcohol chiral ligands has been accomplished, and the polymers have been used as ligands for the catalytic asymmetric addition of diethylzinc to benzaldehyde, giving up to 89% ee. Incorporation onto a polymer support prevents the variation of ee with time that is observed in reactions of one unsupported ligand, perhaps as a result of site isolation of the ligand within the polymer, preventing cooperative effects. Copyright Taylor & Francis Group, LLC.
- Page, Philip C. Bulman,Allin, Steven M.,Dilly, Suzanne J.,Buckley, Benjamin R.
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p. 2019 - 2030
(2008/02/05)
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- Total synthesis of the cytotoxic cyclopeptide mollamide, isolated from the sea squirt Didemnum molle
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Full details of a total synthesis of the novel reverse prenyl substituted cyclic peptide mollamide, isolated from the ascidian Didemnum molle, are described.
- McKeever, Benedict,Pattenden, Gerald
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p. 2701 - 2712
(2007/10/03)
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- The stereospecific synthesis of 'orthogonally' protected lanthionines
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Lanthionine is an attractive monomer for the design and synthesis of novel conformationally constrained peptidomimetics, since unlike cystine, the monosulfur bridge of lanthionine is chemically far more robust and also displays a greater degree of conformational rigidity. The synthesis of lanthionine residues for use in peptide synthesis is non-trivial due to the protectional requirements necessary for this tetra-functional amino acid. In this paper an efficient stereo-specific route to orthogonally protected lanthionine is described.
- Swali, Vinay,Matteucci, Mizio,Elliot, Richard,Bradley, Mark
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p. 9101 - 9109
(2007/10/03)
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- A new and expeditious asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic acids from chiral amino alcohols
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The mechanism for the transformation of β-amino alcohol methanesulfonate hydrochlorides into sodium β-amino alkanesulfonates using sodium sulfite was investigated. The results show that sodium sulfite initially neutralizes the β-amino alcohol methanesulfonate hydrochloride to give a free β-amino alcohol methanesulfonate, which then cyclizes to a 2-alkylaziridine. Attack by the previously formed sodium bisulfite at the less hindered carbon atom of the aziridine ring then yields a β-amino alkanesulfate sodium salt. Based on this mechanistic proposal, a new and rapid asymmetric synthesis of (R)- and (S)-2-aminoalkanesulfonic acids from chiral amino alcohols was developed. Chiral amino alcohols were converted to chiral aziridines through the Wenker method or Mitsunobu reaction and the resulting aziridines were reacted with sodium bisulfite to produce chiral β-amino alkanesulfonic acids.
- Xu, Jiaxi
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p. 1129 - 1134
(2007/10/03)
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- A convenient method of preparing optically active (S)-N-tritylaziridine- 2-carboxylate esters from (S)-β-haloamino acids
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A convenient method of preparing optically active (S)-N-tritylaziridine- 2-carboxylate esters via intramolecular cyclization of (S)-N-trityl-β- haloamino acid esters is described.
- Kato, Yasuo,Fukumoto, Kenji
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p. 245 - 246
(2007/10/03)
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- Total synthesis of mollamide, a reverse prenyl substituted cytotoxic cyclic peptide from Didemnum molle
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A total synthesis of the novel reverse prenyl substituted cyclic peptide mollamide, isolated from the ascidian Didemnum molle, is described.
- McKeever, Benedict,Pattenden, Gerald
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p. 9317 - 9320
(2007/10/03)
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- Synthesis of natural and non natural orthogonally protected lanthionines from N-tritylserine and allo-threonine derivatives
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The reactivity of electrophiles derived from N-tritylserine, threonine and allothreonine esters toward a selection of nucleophiles was investigated. Best yields from substitution products were obtained with N-trityliodoalanine and soft nucleophiles such a
- Dugave, Christophe,Menez, Andre
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p. 1453 - 1465
(2007/10/03)
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- Efficient synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)-hexahydro-1H-1,4-diazepine from methyl (2R)- and (2S)-1-benzyloxycarbonylaziridine-2-carboxylates
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An efficient and practical method for the synthesis of (6R)-6-amino-1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepine 2, which serves as the amine part of DAT-582, a potent and selective 5-HT3 receptor antagonist, is described. The key inte
- Kato, Shiro,Harada, Hiroshi,Morie, Toshiya
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p. 3219 - 3225
(2007/10/03)
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- Synthesis and crystal structure of enantiopure N-tritylaziridin-2-yl-methanols from L-serine and L-threonine
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A convenient multigram 'one pot procedure' for the synthesis of methyl N-tritylaziridine-2-carboxylates 1 and 2, starting from the N-tritylmethyl esters of L-serine 9 and L-threonine 10 and using methanesulfonyl chloride and triethylamine, is described. T
- Willems, Johannes G. H.,Hersmis, Marco C.,De Gelder, Rene,Smits, Jan M. M.,Hammink, Jeannet B.,Dommerholt, F. Jan,Thijs, Lambertus,Zwanenburg, Binne
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p. 963 - 967
(2007/10/03)
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- Versatile synthesis of L-α-amino acids stereospecifically labelled on the β-carbon atom
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Inversion of the stereochemistry at the α-centre of stereospecifically labelled samples of (2S)-isoserine (7) using a sequence involving an intramolecular substitution reaction has allowed synthesis of the stereospecifically labelled aziridines (19) to be completed. These are synthons for a very versatile preparation of L-amino acids which are stereospecifically labelled at the β-carbon atom.
- Beresford, Kenneth J. M.,Young, Douglas W.
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p. 9891 - 9900
(2007/10/03)
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- Asymmetric Ketone Reduction using Chiral Oxazaborolidines derived from Aziridine Carbinols
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Asymmetric borane reduction of acetophenone using 1,3,2-oxazaborolidines derived from aziridine-2-tertiary alcohols 1 and 2 yielded the corresponding alcohol in high optical yields.The synthesis of the novel chiral catalysts 1 and 2 using D-and L-serine,
- Willems, Johannes G. H.,Dommerholt, F. Jan,Hammink, Jeannet B.,Vaarhorst, Ariaela M.,Thijs, Lambertus,Zwanenburg, Binne
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p. 603 - 606
(2007/10/02)
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- Synthesis of Amino Acids with Modified Principal Properties 2: Amino Acids with Polar Side Chains
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The synthesis and characterization of five new homochiral amino acids derived from L-serine are presented.In the modified amino acids, the side chain of serine has been elongated by the introduction of one or more ethyleneoxy moieties and the new compounds contain either a terminal hydroxy group or a terminal amino group.Full experimental details are given for the synthesis of the following amino acids: (2S)-2-amino-6-hydroxy-4-oxahexanoic acid, (2S)-2-amino-9-hydroxy-4,7-dioxanonanoic acid, (2S)-2-amino-12-hydroxy-4,7,10-trioxadodecanoic acid, (2S)-2,9-diamino-4,7-dioxanonanoic acid, and (2S)-2,12-diamino-4,7,10-trioxadodecanoic acid.These compounds were prepared with a view to obtaining amino acids which possess physical and chemical properties such that their principal properties would be different from previously known amino acids.The structural modifications were made with the objective of altering the principal properties related both to lipophilicity and to size.The principal properties are determined as latent variables in the principal component analysis of molecular property descriptors.Three new amino acids, (2S)-2-amino-9-hydroxy-4,7-dioxanonanoic acid, (2S)-2-amino-12-hydroxy-4,7,10-trioxadodecanoic acid and (2S)-2,12-diamino-4,7,10-trioxadodecanoic acid were found to have principal properties which are clearly different from those of previously known amino acids.The principal properties as measured by the principal component scores are given.
- Larsson, Ulf,Carlson, Rolf
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p. 511 - 516
(2007/10/02)
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- Amino Acid Synthesis via Ring Opening of N-Sulphonyl Aziridine-2-Carboxylate Esters with Organometallic Reagents.
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Nucleophilic ring opening of optically active N-sulphonyl aziridine-2-carboxylate esters with organometallic reagents has been investigated as a method of preparation of optically active amino acids.Key Words: aziridine-2-carboxylate, cuprate, nucleophilic ring opening, amino acid
- Baldwin, Jack E.,Spivey, Alan C.,Schofield, Christopher J.,Sweeney, Joseph B.
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p. 6309 - 6330
(2007/10/02)
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