- Amino [13]-macrodilactones: Synthesis, derivatization, and structural motifs
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Macrocycles draw their usefulness from an ability to balance size, shape, and functionality according to general principles. These structural parameters manifest as the conformations of macrocycles and ultimately their functions. Reported here are results of an investigation on [13]-macrodilactones that take up unique folded conformations based on the interplay of multi-atom planar units and sterics. The defining feature of this group of [13]-macrodilactones is the pendant amine group attached to the ring. Amidation of the ring generated analogs that were designed to imitate features of the macrocyclic natural product Teixobactin. We also show that intramolecular interactions, and the A-value of an acylated amine can explain the conformational preferences in macrocycles.
- Chen, Chengsheng,Lawrence, Jean-Marc,Peczuh, Mark W.
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- Zinc mediated addition of active halides to a glycine cation equivalent: Synthesis of N-Boc-L-propargylglycine
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The reaction of allylic, benzylic and propargylic halides with zine in the presence of the glycine cation equivalent, methyl N-Boc-2-acetoxyglycine, affords Boc protected amino acid derivatives in high yield. Resolution of methyl N-Boc- propargylglycine w
- Abood, Norman A.,Nosal, Roger
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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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- THERAPEUTIC OR PROPHYLACTIC AGENT FOR ALLERGIC DERMATITIS
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A therapeutic or prophylactic agent for allergic dermatitis is disclosed. The therapeutic or prophylactic agent comprises as an effective ingredient a glycine derivative having a specific structure or a pharmaceutically acceptable salt thereof, for example, the below-described compound [(E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid]. The therapeutic or prophylactic agent for allergic dermatitis according to the present invention has high therapeutic or prophylactic effect.
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Page/Page column 37
(2009/04/23)
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- THERAPEUTIC OR PROPHYLACTIC AGENT FOR MULTIPLE SCLEROSIS
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A therapeutic or prophylactic agent for multiple sclerosis is disclosed. The therapeutic or prophylactic agent comprises as an effective ingredient a glycine derivative having a specific structure or a pharmaceutically acceptable salt thereof, for example, the below-described compound [(E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid]. The therapeutic or prophylactic agent for multiple sclerosis according to the present invention shows the excellent absorbability and in vivo stability when orally administered, and exhibits high therapeutic or prophylactic effects.
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Page/Page column 37
(2009/04/23)
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- 3,5-DIAMINO-6-CHLORO-PYRAZINE-2-CARBOXYLIC ACID DERIVATIVES AND THEIR USE AS EPITHELIAL SODIUM CHANNEL BLOCKERS FOR THE TREATMENT OF ARWAY DISEASES
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A compound of Formula (I) in free or salt or solvate form, where R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the meanings as indicated in the specification, is useful for treating diseases which respond to the blockade of the epithelial sodium channel. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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- Ring-opening Cross-metathesis (ROCM) as a novel tool for the ligation of peptides
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The development of ring-opening cross-metathesis (ROCM) as a novel tool for the site-specific ligation of peptide units is reported. The resulting structural units at the site of ligation resulting from ROCM resemble proline as well as other known ss-turn
- Michaelis, Simon,Blechert, Siegfried
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p. 2358 - 2368
(2008/02/04)
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- SUBSTITUTED AMINO CARBOXYLIC ACIDS
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Disclosed are compounds and pharmaceutically acceptable salts of formula (I): which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.
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Page/Page column 204-205
(2008/06/13)
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- GLYCINE DERIVATIVE AND USE THEREOF
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A glycine derivative which is, e.g., the following compound (Chemical formula (1)). It is highly effective in the treatment and prevention of inflammatory bowel diseases. Compared to conventional compounds, the compound is excellent in absorbability in oral administration and in vivo stability. The compound can be orally administered and can retain an excellent therapeutic or preventive effect over a longer period.
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Page/Page column 57
(2008/06/13)
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- RCM-mediated synthesis of trifluoromethyl-containing nitrogen heterocycles
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(Chemical Equation Presented) A ring-closing metathesis mediated pathway to trifluoromethyl-containing piperidines is detailed. This involves the development of a synthetic route to a new (trifluoromethyl)allylating reagent via a Diels-Alder/retro-Diels-Alder strategy, its application in the synthesis of a series of trifluormethyl-substituted diolefin recursors for ring-closing metathesis, and eventually the successful cyclization of these precursor molecules into the corresponding functionalized piperidines.
- De Matteis, Valeria,Van Delft, Floris L.,Jakobi, Harald,Lindell, Stephen,Tiebes, Joerg,Rutjes, Floris P. J. T.
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p. 7527 - 7532
(2007/10/03)
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- Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists
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The two diastereomeric pairs of acidic amino acids 5-(2-amino-2- carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid (8A/8B) and 4-(2-amino-2-carboxyethyl)-5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid (10A/10B) were prepared via a strategy based on a 1,3-dipolar cycloaddition. The four amino acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/SB showed a remarkable affinity, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (Ki values 0.21 and 0.96 ìè, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity in in vivo tests on DBA/2 mice. Derivative 10A was inactive at all ionotropic glutamate receptors, whereas its stereoisomer 10B displayed a seizable binding to both NMDA and AMPA receptors.
- Conti, Paola,De Amici, Marco,Grazioso, Giovanni,Roda, Gabriella,Negra, Federico F. Barberis,Nielsen, Birgitte,Stensb?l, Tine B.,Madsen, Ulf,Br?uner-Osborne, Hans,Frydenvang, Karla,De Sarro, Giovambattista,Toma, Lucio,De Micheli, Carlo
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p. 6740 - 6748
(2007/10/03)
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- Stereospecific synthesis of chiral N-(ethynyl)allylglycines and their use in highly stereoselective intramolecular Pauson-Khand reactions
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The first synthesis of an enantiopure N-ethynylated allylglycine and its application in the intramolecular Pauson-Khand reaction, which leads to a novel highly functionalised proline derivative with complete control of stereoselectivity, is reported.
- Witulski, Bernhard,Goessmann, Matthias
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p. 1879 - 1880
(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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- One-Pot Transformation of Benzyl Carbamates into t-Butyl Carbamates
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An N-Cbz group is transformed into an N-Boc group in a single step by transfer hydrogenation in the presence of Boc2O.Functional groups such as Bn, BOM and TBDMS ethers are stable under the reaction conditions. Key Words: Transformation; benzyl carbamate;
- Bajwa, Joginder S.
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p. 2955 - 2956
(2007/10/02)
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- Syntheses and Reactions of Silyl Carbamates. 1. Chemoselective Transformation of Amino Protecting Groups via tert-Butyldimethylsilyl Carbamates
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The N-tert-butyldimethylsilyloxycarbonyl group (silyl carbamate) was synthesized from commonly used amino protecting groups such as N-tert-butoxycarbonyl (Boc) and N-benzyloxycarbonyl (Z) by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate/2,6-lutidine and tert-butyldimethylsilane/Pd(OAc)2, respectively.This novel species, upon activation with fluoride ion, reacts with a variety of electrophiles to give N-ester type compounds in high yield.For example, the conversion of N-t-Boc compounds into their corresponding N-Z compounds via a silyl carbamate was accomplished under these mild reaction conditions.
- Sakaitani, Masahiro,Ohfune, Yasufumi
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p. 870 - 876
(2007/10/02)
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- MOLECULAR MODELING OF γ-LACTAM ANALOGUES OF β-LACTAM ANTIBACTERIAL AGENTS: SYNTHESIS AND BIOLOGICAL EVALUATION OF SELECTED PENEM AND CARBAPENEM ANALOGUES
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Computational chemistry made possible the prediction of the three-dimensional structures of γ-lactam analogues of penems and carbapenems before the analogues were made.Molecular superpositioning showed that these novel structures with a 7β-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics.This suggest that 8-oxo-7-acylamino-1-azabicyclooct-2-ene-2-carboxylates and 4-thia-analogues can be accommodated in the same active sites of essential bacterical penicillin-binding proteins where cephalosporins and penicillins are recognized.The syntheses of these compounds are reported.The γ-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other γ-lactams.
- Allen, Norris E.,Boyd, Donald B.,Campbell, Jack B.,Deeter, Jack B.,Elzey, Thomas K.,et al.
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p. 1905 - 1928
(2007/10/02)
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