- Aliphatic chain-containing macrocycles as diazonamide A analogs
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[Figure not available: see fulltext.] Aliphatic alkyl chain-containing 12–14-membered macrocycles have been designed as structural analogs of antimitotic natural product diazonamide A. Macrocycles were synthesized from 5-bromooxazole in 7 to 9 linear step
- Vitkovska, Viktorija,Zogota, Rimants,Kalnins, Toms,Zelencova, Diana,Suna, Edgars
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p. 586 - 602
(2020/06/10)
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- MODULATORS OF THE INTEGRATED STRESS RESPONSE PATHWAY
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1 to R3, A1 and A2 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating and preventing one or more diseases or disorders associated with integrated stress response.
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- MODULATORS OF THE INTEGRATED STRESS PATHWAY
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Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.
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Page/Page column 165
(2019/05/22)
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- Z-SELECTIVE OLEFIN METATHESIS OF PEPTIDES
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The invention relates generally to the synthesis of modified amino acids and modified peptides in the presence of cyclometalated catalysts. The invention has utility in the fields of catalysis, organic synthesis, polymer chemistry, and industrial and fine
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- Synthesis of ω-Oxo Amino Acids and trans-5-Substituted Proline Derivatives Using Cross-Metathesis of Unsaturated Amino Acids
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A range of 7-oxo, 8-oxo, and 9-oxo amino acids, analogues of 8-oxo-2-aminodecanoic acid, one of the key components of the cyclic tetrapeptide apicidin, have been prepared by a three-step process involving copper-catalyzed allylation of serine-, aspartic acid-, and glutamic acid-derived organozinc reagents, followed by cross-metathesis of the resulting terminal alkenes with unsaturated ketones and hydrogenation. The intermediate 7-oxo-5-enones underwent a highly diastereoselective (dr ≥96:4) acid-catalyzed aza-Michael reaction to give trans-2,5-disubstituted pyrrolidines, 5-substituted proline derivatives. The aza-Michael reaction was first observed when the starting enones were allowed to stand in solution in deuterochloroform but can be efficiently promoted by catalytic amounts of dry HCl.
- Salih, Nabaz,Adams, Harry,Jackson, Richard F. W.
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p. 8386 - 8393
(2016/09/28)
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- Insight into Transannular Cyclization Reactions to Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams
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An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions. (Chemical Equation Presented).
- Atmuri, N. D. Prasad,Lubell, William D.
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p. 4904 - 4918
(2015/06/02)
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- Z-selective olefin metathesis on peptides: Investigation of side-chain influence, preorganization, and guidelines in substrate selection
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Olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds; however, the ability to control olefin geometry in the product remains a challenge. Recent advances in the design of cyclom
- Mangold, Shane L.,Oleary, Daniel J.,Grubbs, Robert H.
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p. 12469 - 12478
(2014/11/07)
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- Synthesis of the unusual α-amino acid component of some novel histone deacetylase inhibiting cyclic peptides
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A flexible protocol for the synthesis of three lipophilic α-amino acid components of some novel cyclic peptides having important histone deacetylase inhibiting properties has been developed from a common source, which featured a cross-metathesis reaction
- Pahari, Amit K.,Mukherjee, Jyoti Prasad,Chattopadhyay, Shital K.
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p. 7185 - 7191
(2017/09/12)
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- Flexible synthesis and evaluation of diverse anti-apicomplexa cyclic peptides
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A modular approach to synthesize anti-Apicomplexa parasite inhibitors was developed that takes advantage of a pluripotent cyclic tetrapeptide scaffold capable of adjusting appendage and skeletal diversities in only a few steps (one to three steps). The diversification processes make use of selective radical coupling reactions and involve a new example of a reductive carbon-nitrogen cleavage reaction with SmI2. The resulting bioactive cyclic peptides have revealed new insights into structural factors that govern selectivity between Apicomplexa parasites such as Toxoplasma and Plasmodium and human cells.
- Traore, Mariam,Mietton, Flore,Maubon, Daniele,Peuchmaur, Marine,Francisco Hilario, Flaviane,Pereira De Freitas, Rossimiriam,Bougdour, Alexandre,Curt, Aurelie,Maynadier, Marjorie,Vial, Henri,Pelloux, Herve,Hakimi, Mohamed-Ali,Wong, Yung-Sing
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p. 3655 - 3675
(2013/07/04)
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- New histone deacetylase inhibitors based on 4-fluoro-2-amino acid esters: Synthesis and activity
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A series of twelve fluorinated and non-fluorinated potential histone deacetylase inhibitors 25 was synthesized and their inhibitory activity was tested against rat liver histone deacetylase. The new inhibitors involve an enzyme binding element consisting of asparagine, glutamine or different short chain fluorinated or unfluorinated amino acids, a suberoyl spacer and a hydroxamic acid functionality, which is responsible for the inhibitory activity. The 4-fluoro-2-aminobutyric acid esters 1a,b, their 2-methyl derivatives 2a,b and the 2-amino-4-fluoropent-4-enoic acid esters 3a,b were synthesized by alkylation of glycine or alanine ester imides with bromofluoroethane or 2-fluoroallylbromide, respectively. Methyl 2-amino-5-fluorohex-5-enoate (4a) was prepared using 3-fluorobut-3-enyl tosylate or the iodide as alkylating reagents. An alternative pathway starting from Boc protected 3-iodo-L-alanine was more efficient. The latter method was also applied to synthesize the parent unfluorinated compound 4c using allylbromide as the alkylating reagent. The fluorinated compounds, tested as histone deacetylase inhibitors were slightly less active than comparable (S)-valine, (S)-phenylalanine or (S)-allylglycine derivatives that do not contain a fluorine atom. Interestingly, it was shown for the first time that the fluoro vinyl group which was proposed to be an aprotic amide mimic due to its electronic properties may serve as a bioisosteric replacement of a primary amide function. For the fluorinated analogs 25f (IC50 0.88 μM) and 25i (IC50 1.02 μM) a similar or an even enhanced inhibitory activity was observed compared to the unfluorinated parents 25g (IC50 0.67 μM) and 25j (IC50 1.79 μM) or the (S)-asparagine or (S)-glutamine derivatives 25l (IC50 2.10 μM) and 25m (IC50 3.90 μM).
- Lübke, Martin,Jung, Manfred,Haufe, Günter
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p. 144 - 156
(2013/11/06)
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- Native chemical ligation, thiol-ene click: A methodology for the synthesis of functionalized peptides
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The sequential combination of native chemical ligation and thiol-ene radical chemistry (NCL-TEC) on the resulting cysteine thiol has been investigated as a methodology for rapidly accessing functionalized peptides. Three sequential cycles of native chemical ligation and subsequent thiyl radical reactions (including a free-radical-mediated desulfurization reaction) were carried out on a peptide backbone demonstrating the iterative nature of this process. The versatility of the thiyl radical reaction at cysteine was demonstrated through the introduction of a number of different side chains including an amino acid derivative, a carbohydrate group, and an alkyl azide. Conditions were developed that allowed the sequential NCL-TEC process to proceed in high yield.
- Markey, Lyn,Giordani, Silvia,Scanlan, Eoin M.
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p. 4270 - 4277
(2013/06/27)
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- CYCLIC PEPTIDES WITH AN ANTI-PARASITIC ACTIVITY
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The present invention relates to a method for preparing a cyclic peptide with antiparasite activity and anticancer activity. The invention also relates to this peptide as an antiparasite agent, for example in the treatment of toxoplasmosis and as an antic
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Page/Page column 6
(2012/02/15)
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- Pd-catalyzed carboamination of oxazolidin-2-ones: A stereoselective route to trans -2,5-disubstituted pyrrolidines
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Palladium-catalyzed carboamination reactions between aryl bromides and 4-(but-3-enyl)-substituted oxazolidin-2-ones are described. These transformations afford bicyclic oxazolidin-2-one derivatives that can be converted to trans-2,5-disubstituted pyrrolid
- Lemen, Georgia S.,Wolfe, John P.
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supporting information; experimental part
p. 2322 - 2325
(2010/07/14)
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- Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of β-secretase (BACE1)
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Cyclization of recently reported linear phosphino dipeptide isostere inhibitors of BACE1 via side chain olefin metathesis yielded macrocyclic BACE1 inhibitors. The most potent compound II-P1 (IC50 of 47 nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44 min for the macrocyclic inhibitor II-P1 compared to the linear compound I.
- Huber, Timo,Manzenrieder, Florian,Kuttruff, Christian A.,Dorner-Ciossek, Cornelia,Kessler, Horst
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supporting information; experimental part
p. 4427 - 4431
(2010/04/05)
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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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- Macrocyclic peptidomimetic inhibitors of β-secretase (BACE): First X-ray structure of a macrocyclic peptidomimetic-BACE complex
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The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 A resolution. This molecule inhibits the production of the Aβ peptide in HEK293 cells overexpressing APP751sw.
- Rojo, Isabel,Martin, Jose Alfredo,Broughton, Howard,Timm, David,Erickson, Jon,Yang, Hsiu-Chiung,McCarthy, James R.
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p. 191 - 195
(2007/10/03)
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- S-adenosylhomocysteine analogues with the carbon-5′ and sulfur atoms replaced by a vinyl unit
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(Chemical Equation Presented) Cross-metathesis of suitably protected 5′-deoxy-5′-methyleneadenosines with racemic and chiral N-Boc-protected six-carbon amino acids bearing a terminal double bond in the presence of the Hoveyda-Grubbs catalyst gave adenosyl
- Andrei, Daniela,Wnuk, Stanislaw F.
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p. 5093 - 5096
(2007/10/03)
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- A new selective cleavage of N,N-dicarbamoyl-protected amines using lithium bromide
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A mild and new procedure for the selective cleavage of an alkoxycarbonyl group (Boc, CBz) in N,N-dicarbamoyl-protected amino compounds is described. The method is based on the use of lithium bromide in acetonitrile and is compatible with a large range of other functionalities present in the substrates. Compared with other reported methodologies, the procedure is particularly useful for the Cbz-selective cleavage in N,N-Ts,Cbz-diprotected amines. A rationalization of the selectivity supported by ab initio calculations is also presented.
- Hernandez, J. Nicolas,Ramirez, Miguel A.,Martin, Victor S.
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p. 743 - 746
(2007/10/03)
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- Combined application of organozinc chemistry and one-pot hydroboration-Suzuki coupling to the synthesis of amino acids
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Hydroboration using 9-BBN-H of the protected enantiomerically pure but-3-enylglycine derivative 11, prepared by copper-catalysed allylation of the serine-derived organozinc reagent 1, followed by Suzuki coupling of the derived borane with a variety of aromatic halides, 2-bromopyridine and 2-bromopropene gives the protected amino acids 14a-1 and 15. This method augments our previous methods for the synthesis of phenylalanine homologues.
- Rodriguez, Arantxa,Miller, David D.,Jackson, Richard F.W.
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p. 973 - 977
(2007/10/03)
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- Beta-amino acid derivatives useful for the treatment of bacterial infections
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The invention provides compounds that are useful for the treatment of bacterial infections in mammals. More specifically, it is directed to beta-amino acid derivatives or pharmaceutically acceptable salts, prodrugs, or isomers of those compounds that are
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- Enantioselective synthesis of unsaturated amino acids using p- methoxybenzylamine as an ammonia equivalent
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A versatile, non-alkylative enantioselective synthesis of unsaturated α-amino acids based on the Sharpless asymmetric epoxidation has been developed. Enantiomerically enriched trans epoxy alcohols bearing unsaturated substituents were prepared and submitted to regio- and stereospecific ring- opening with p-methoxybenzylamine as a nucleophile, leading to anti-3-(p- methoxybenzylamino)-1,2-diols which were further protected by reaction with Boc2O. The 1,2-diol fragment was then oxidatively cleaved by a sequential treatment with sodium periodate and sodium chlorite to afford the corresponding amino acid. Using this methodology, doubly N-protected (p- methoxybenzyl and Boc) allyl glycine, 3-butenyl glycine and 4-pentenyl glycine have been prepared in three synthetic steps from the corresponding allyl alcohols. As a demonstration of the orthogonal nature of the nitrogen protection, both protecting groups have been selectively removed from the fully protected amino ester. (C) 1999 Elsevier Science Ltd.
- Alcon, Montserrat,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 4639 - 4651
(2007/10/03)
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- Design, synthesis, and conformational analysis of a proposed type I β- turn mimic
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In an effort to design a dipeptide structural mimic of protein and peptide β-turns, we have prepared and evaluated the conformation of derivatives of the novel, highly constrained ten-membered lactam, (3S,10S)- (6E)-2-azacyclodec-6-enone (1). A synthetic
- Fink, Brian E.,Kym, Phil R.,Katzenellenbogen, John A.
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p. 4334 - 4344
(2007/10/03)
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- Cross-metathesis of unsaturated α-amino acid derivatives
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Cross-metathesis of homoallylglycine derivatives with aryl- and alkyl-substituted alkenes using the ruthenium catalyst (Cy3P)2Cl2Ru=CHPh 1 has been achieved in 43-55 and 55-66% yield respectively. Allylglycine, vinylglycine and dehydroalanine derivatives have also been examined. Whilst cross-metathesis of allylglycine derivatives with alkyl-substituted alkenes using catalyst 1 may be regarded as a synthetically useful procedure, cross-metathesis reactions of vinylglycine and dehydroalanine derivatives using catalyst 1 are non-viable. Attachment of FmocHagOH 13 to a capped Wang resin, cross-metathesis with dodec-1-ene, and product removal from the resin gives the cross-metathesis product in 74% yield based on FmocHagOH.
- Biagini, Stefano C. G.,Gibson, Susan E.,Keen, Stephen P.
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p. 2485 - 2499
(2007/10/03)
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- Synthesis of Enantiomerically Pure Unsaturated α-Amino Acids Using Serine-Derived Zinc/Copper Reagents
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Treatment of the serine-derived organozinc reagent 2, in benzene/dimethylacetamide, with a THF solution of CuCN*2LiCl gives rise to a zinc/copper reagent 6 which reacts directly with allylic halides and tosylates to give the corresponding enantiomerically pure substitution products 9 in 32-65percent yield (11 examples).The reaction proceeds by formal SN2' displacement of the leaving group.Reaction with propargyl halides gives the corresponding terminal allene 12a.The zinc reagent 2 may also be prepared directly from protected iodoalanine 1 in THF by the Knochel method.Reaction with propargylic tosylates as electrophiles gives rise to the corresponding protected terminal allenic amino acids in 51-81percent yield (four examples); use of enantiomerically enriched propargylic tosylates results in the formation of diastereoisomerically enriched allenic products.Reactions of the zinc/copper reagent 6 with a range of representative electrophiles is explored; use of relatively reactive electrophiles is necessary to obtain satisfactory yields.Finally, the possibility of using the serine-derived iodide 20, in which the carboxylic acid is protected as a methyl ester, is established.This reagent offers advantages over the corresponding benzyl ester protected reagent 6 for the synthesis of unsaturated amino acids.
- Dunn, Michael J.,Jackson, Richard F. W.,Pietruszka, Joerg,Turner, Debra
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p. 2210 - 2215
(2007/10/02)
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- LES ORGANOCUPRATES DANS UNE NOUVELLE SYNTHESE D'AMINOACIDES ENANTIOMERIQUEMENT PURS
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A new general method of synthesis of optically pure α- amino esters was elaborated during studies on the reaction of organocuprates with tosyl and halogeno derivatives of L-serine and L-homoserine.
- Bajgrowicz, J. A.,Hallaoui, A. El,Jacquier, R.,Pigiere, Ch.,Viallefont, Ph.
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p. 1833 - 1845
(2007/10/02)
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- ORGANOCUPRATES MEDIATED CARBON-CARBON BOND FORMATION IN γ POSITION OF α-AMINO ESTERS WITHOUT RACEMISATION
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A new general method of synthesis of optically pure α-amino esters by action of organocuprates on t-butyloxycarbonyl-L-α-amino-γ-bromobutyric acid methyl ester is described.
- Bajgrowicz, J. A.,Hallaoui El, A.,Jacquier, R.,Pigiere, Ch.,Viallefont, Ph.
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p. 2231 - 2234
(2007/10/02)
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