- Stereoselective synthesis of Boc-protected L-seleno- and tellurolanthionine, L-seleno- and tellurocystine and derivatives
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Optically active seleno- and telluro amino acids can be synthesized from serine via its β-lactone with selenides and tellurides under overall retention of the serine stereochemistry. Boc-protected l-selenolanthionine, l-tellurolanthionine, l-selenocystine
- Schneider, Alex,Rodrigues, Oscar E. D.,Paix?o, Márcio W.,Appelt, Helmoz R.,Braga, Antonio L.,Wessjohann, Ludger A.
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Read Online
- Parallel solid synthesis of inhibitors of the essential cell division FtsZ enzyme as a new potential class of antibacterials
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As a model system for designing new inhibitors of bacterial cell division, we studied the essential and highly conserved FtsZ GTPase from Pseudomonas aeruginosa. A collection of GTP analogues were prepared using the solid-phase parallel synthesis approach. The synthesized GTP analogues inhibited the GTPase activity of FtsZ with IC50 values between 450 μM and 2.6 mM, and 5 compounds inhibited Staphylococcus aureus growth in a biological assay. The FtsZ spectrophotometric assay developed for screening of synthesized compounds is the first step in identification of antibacterials targeting the bacterial cell division essential proteins.
- Paradis-Bleau, Catherine,Beaumont, Melanie,Sanschagrin, Francois,Voyer, Normand,Levesque, Roger C.
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Read Online
- Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site
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Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin?GB1 complex.
- Matthew, Susan,Chen, Qi-Yin,Ratnayake, Ranjala,Fermaintt, Charles S.,Lucena-Agell, Daniel,Bonato, Francesca,Prota, Andrea E.,Lim, Seok Ting,Wang, Xiaomeng,Díaz, J. Fernando,Risinger, April L.,Paul, Valerie J.,Oliva, Maria ángela,Luesch, Hendrik
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- Exploring the dNTP -binding site of HIV-1 reverse transcriptase for inhibitor design
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HIV-1 reverse transcriptase (RT) plays a central role in the viral life cycle, and roughly half of the FDA-approved anti-HIV drugs are targeting RT. Nucleoside analogs (NRTIs) require cellular phosphorylation for binding to RT, and to bypass this rate-limiting path, we designed a new series of acyclic nucleoside phosphonate analogs as nucleoside triphosphate mimics, aiming at the chelation of the catalytic Mg2+ ions via a phosphonate and/or a carboxylic acid group. Novel synthetic procedures were developed to access these nucleoside phosphonate analogs. X-ray structures in complex with HIV-1 RT/dsDNA demonstrated that their binding modes are distinct from that of our previously reported compound series. The impact of chain length, chirality and linker atom have been discussed. The detailed structural understanding of these new compounds provides opportunities for designing new class of HIV-1 RT inhibitors.
- Gu, Weijie,Martinez, Sergio,Singh, Abhimanyu K.,Nguyen, Hoai,Rozenski, Jef,Schols, Dominique,Herdewijn, Piet,Das, Kalyan,De Jonghe, Steven
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- PNA Hybrid Sequences as Recognition Units in SNARE-Protein-Mimicking Peptides
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Membrane fusion is an essential process in nature and is often accomplished by the specific interaction of SNARE proteins. SNARE model systems, in which SNARE domains are replaced by small artificial units, represent valuable tools to study membrane fusio
- Hubrich, Barbara E.,Kumar, Pawan,Neitz, Hermann,Grunwald, Matthias,Grothe, Tobias,Walla, Peter Jomo,Jahn, Reinhard,Diederichsen, Ulf
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supporting information
p. 14932 - 14936
(2018/10/15)
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- Synthesis and characterization of selenium(I/II) and tellurium(IV) derivatives of amino acids
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The direct reaction between Te metal and methyl 2-(2-bromoacetamido)propanoate (27) at room temperature, yields the first example of organotellurium(IV) derivative (MeOC(O)CH(Me)NHCOCH2)2TeBr2 (31). Similarly, reaction of Te with methyl 2-(2-bromoacetamido)acetate (26) and methyl 2-(2-bromoacetamido)-3-phenylpropanoate (28) in presence of NaI in acetone gives MeOC(O)CH2NHCOCH2I (29), MeOC(O)CH(R)NHCOCH2)2TeI2 (R = H (30) and CH2Ph (32). Treatment of 26/27/28 with Li2Te2/Li2Se2 readily provides the [MeOC(O)CH(CH3)NHCOCH2]2Te2, (33); [MeOC(O)CH2NHCOCH2]2Se2, (34); [MeOC(O)CH(CH2Ph)NHCOCH2]2Se2, (35) and [Figure presented] (36). Similarly the reaction of (2,6-dimethyl-4-tert-butylC6H2)SeNa with 28 readily provide the [MeOC(O)CH(CH2Ph)NHCOCH2]SeC6H2-2,6-dimethyl-4-tert-butyl), (37) in good yield. Molecule [MeOC(O)CHNH(Boc)CH2]2Se2, (38) and [NaOC(O)CHNH(Boc)CH2Te(2,4,6-Me3C6H2] (39) were prepared by the treatment of Li2Se2/2,4,6-Me3C6H2TeNa with methyl 3-bromo-2-((tert-butoxycarbonyl)amino)propanoate and N-(t-Boc)-L-serine β-lactone respectively. These compounds are purified by chromatography and characterized by a number of analytical techniques such as (1H, 13C, 77Se and 125Te NMR) spectroscopy, mass spectrometry and elemental analysis. The single crystal X-ray studies of 29, 30, 31, 36 and 38 revealed the presence of characteristic O?Se/Te, secondary bonding interactions. A detailed analysis of the crystal structures of the compound reveals interesting supramolecular assembly.
- Singh, Puspendra,Singh, Harkesh B.,Butcher, Ray J.
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- ANTIBACTERIAL COMPOUNDS
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Novel compounds having antimicrobial activitiy, in particular against Pseudomonas aeruginosa, Burkholderia cepaciaand/or Clostridium difficile, and a pharmaceutical composition containing the novel compound.
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Page/Page column 28
(2018/10/19)
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- ISOBARIC MASS LABELS
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The present invention relates to a set of two or more mass labels, wherein each mass label comprises the formula: [in-line-formulae]X-L-M-Re[/in-line-formulae] wherein X is a reporter moiety having an exact mass, L is a bond cleavable by collision in a ma
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Paragraph 0023; 0174
(2019/01/04)
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- Purine alanine derivative used for tumor therapy, and preparation method and application of derivative
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The invention discloses a purine alanine derivative used for tumor therapy, and a preparation method and an application of the derivative, and belongs to the technical field of synthesis of antitumor medicines. The purine alanine derivative used for tumor
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Paragraph 0019; 0023; 0026
(2017/06/02)
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- Synthesis and pharmacological characterization of the selective GluK1 radioligand (: S)-2-amino-3-(6-[3H]-2,4-dioxo-3,4-dihydrothieno[3,2- d] pyrimidin-1(2 H)-yl)propanoic acid ([3H]-NF608)
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The kainic acid receptors belong to the class of ionotropic glutamate receptors and comprise five subunits named GluK1-5. Radioligands are essential tools for use in binding assays aimed at ligand-receptor structure-activity-relationship studies. Previous work has led to the synthesis of GluK1 radioligands [3H]-SYM2081, [3H]-UBP310 and [3H]-ATPA, however all strategies were work-intensive and thus not attractive. Herein, we report the synthesis of [3H]-NF608 and subsequent pharmacological evaluation at homomeric recombinant rat GluK1 receptors. Binding affinities of a series of standard GluK1 ligands were shown to be in line with previously reported affinities obtained by use of already reported radioligands.
- Alcaide, Anna,Marconi, Laura,Marek, Ales,Haym, Isabell,Nielsen, Birgitte,M?llerud, Stine,Jensen, Mikael,Conti, Paola,Pickering, Darryl S.,Bunch, Lennart
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p. 2136 - 2144
(2016/11/17)
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- Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes
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A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles without any significant loss of selectivity.
- Cortes-Clerget, Margery,Gager, Olivier,Monteil, Maelle,Pirat, Jean-Luc,Migianu-Griffoni, Evelyne,Deschamp, Julia,Lecouvey, Marc
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supporting information
p. 34 - 40
(2016/01/25)
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- Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase
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Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effec
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Page/Page column 9
(2016/05/19)
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- Nonsymmetrical azocarbonamide carboxylates as effective Mitsunobu reagents
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A family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.
- Furkert, Daniel P.,Breitenbach, Benjamin,Juen, Ludovic,Sroka, Ina,Pantin, Mathilde,Brimble, Margaret A.
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supporting information
p. 7806 - 7809
(2015/02/02)
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- N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships
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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
- Duranti, Andrea,Tontini, Andrea,Antonietti, Francesca,Vacondio, Federica,Fioni, Alessandro,Silva, Claudia,Lodola, Alessio,Rivara, Silvia,Solorzano, Carlos,Piomelli, Daniele,Tarzia, Giorgio,Mor, Marco
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scheme or table
p. 4824 - 4836
(2012/07/03)
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- MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS
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The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.
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(2010/04/30)
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- Synthesis and structure - Activity relationships of N -(2-Oxo-3-oxetanyl) amides as N -acylethanolamine-hydrolyzing acid amidase inhibitors
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The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator- activated receptor-α, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine- hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of β-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.
- Solorzano, Carlos,Antonietti, Francesca,Duranti, Andrea,Tontini, Andrea,Rivara, Silvia,Lodola, Alessio,Vacondio, Federica,Tarzia, Giorgio,Piomelli, Daniele,Mor, Marco
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scheme or table
p. 5770 - 5781
(2010/10/20)
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- Synthesis of epi-oxetin via a serine-derived 2-methyleneoxetane
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(Chemical Equation Presented) The unique reactivity of 2-methyleneoxetanes and 1,5-dioxaspiro[3.2]hexanes has been exploited for the synthesis of epi-oxetin (26), an oxetane-containing β-amino acid. While the preparation of the natural product oxetin (1) was the original goal, the unexpected diastereoselectivity of an precedented reduction provided the epi-oxetin framework. The methodology described herein should be amenable for the preparation of oxetin with a change in nitrogen protection.
- Blauvelt, Marisa L.,Howell, Amy R.
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p. 517 - 521
(2008/09/17)
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- Design and synthesis of intrinsically cell-penetrating nucleopeptides
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Nucleopeptides, which are constituted of α-amino acids bearing nucleobases at their side chains, are able to penetrate into cells and to reach the nucleus without cytotoxic effects. The Royal Society of Chemistry 2008.
- Geotti-Bianchini, Piero,Beyrath, Julien,Chaloin, Olivier,Formaggio, Fernando,Bianco, Alberto
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supporting information; experimental part
p. 3661 - 3663
(2009/02/05)
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- Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV
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Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4- phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity
- Nakatani, Shingo,Hidaka, Koushi,Ami, Ei'Ichi,Nakahara, Koichiro,Sato, Akihiko,Nguyen, Jeffrey-Tri,Hamada, Yoshio,Hori, Yasuko,Ohnishi, Nobuyuki,Nagai, Akinori,Kimura, Tooru,Hayashi, Yoshio,Kiso, Yoshiaki
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scheme or table
p. 2992 - 3004
(2009/04/05)
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- Side chain homologation of alanyl peptide nucleic acids: Pairing selectivity and stacking
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Alanyl peptide nucleic acids (alanyl-PNAs) are oligomers based on a regular peptide backbone with alternating configuration of the amino acids. All side chains are modified by covalently linked nucleobases. Alanyl-PNAs form very rigid, well defined, and l
- Diederichsen, Ulf,Weicherding, Daniel,Diezemann, Nicola
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p. 1058 - 1066
(2007/10/03)
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- 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase
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The present invention relates to certain novel 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase. Pharmaceutical compositions containing said compounds as well as methods of treating various disease states responding to inhibition of matrix metalloproteinase are also claimed herein.
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Page/Page column 50
(2010/02/14)
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- LPA receptor agonists and antagonists and methods of use
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The present invention relates to compounds according to formula (I) as disclosed herein as well as pharmaceutical compositions which include those compounds. Also disclosed are methods of using such compounds, which have activity as agonists or as antagonists of LPA receptors; such methods including inhibiting LPA activity on an LPA receptor, modulating LPA receptor activity, treating cancer, enhancing cell proliferation, and treating a wound.
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- LPA receptor agonists and antagonists and methods of use
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The present invention relates to compounds according to formula (I) as disclosed herein as well as pharmaceutical compositions which include those compounds. Also disclosed are methods of using such compounds, which have activity as agonists or as antagonists of LPA receptors; such methods including inhibiting LPA activity on an LPA receptor, modulating LPA receptor activity, treating cancer, enhancing cell proliferation, treating a wound, treating apoptosis or preserving or restoring function in a cell, tissue, or organ, culturing cells, preserving organ or tissue function, and treating a dermatological condition.
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- Total synthesis of the cyclic peptide Argyrin B
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The details of the total synthesis of Argyrin B, a natural product with immunosuppressive properties, are reported below. The two most unusual amino acid residues of this cyclic peptide are 4-methoxytryptophan and dehydroalanine, which were obtained by mo
- Ley, Steven V.,Priour, Alain
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p. 3995 - 4004
(2007/10/03)
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- A method of using synthetic L-SE-Methylselenocysteine as a nutriceutical and a method of its synthesis
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A synthesis of and use of L-Se-methylselenocysteine as a nutriceutical is described, based upon the knowledge that L-Se-methylselenocysteine is less toxic than L-selenomethionine towards normal cells. The synthesis proceeds by mixing N-(tert-butoxycarbonyl)-L-serine with a dialkyl diazodicarboxylate and at least one of a trialkylphosphine, triarylphosphine and phosphite to form a first mixture that includes N-(tert-butoxycarbonyl)-L-serine β-lactone. Methyl selenol or its salt is mixed with the N-(tert-butoxycarbonyl)-L-serine β-lactone to form a second mixture that includes N-(tert-butoxycarbonyl)-Se-methylselenocysteine. The text butoxycarbonyl group is removed from the N-(tert-butoxycarbonyl)-Se-methylselenocysteine to form L-Se-methylselenocysteine. This synthesis significantly improves the manufacturability, manufacturing efficiency and utility of this naturally occurring rare form of organic-selenium. L-Se-methylselenocysteine formed, for example, in this manner may be used as a nutriceutical for supplementation into the diets of humans or animals for various beneficial purposes, such as, for example, to prevent or reduce the risk of developing cancer.
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- Total synthesis of the cyclic heptapeptide Argyrin B: A new potent inhibitor of T-cell independent antibody formation
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(equation presented) Argyrin B (1) The total synthesis of Argyrin B (1) is presented using a synthetic plan that is convergent and flexible and conserves the stereogenic centers. The unusual amino acid 4-methoxy tryptophan (6) was obtained via an enzymati
- Ley, Steven V.,Prieur, Alain,Heusser, Christoph
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p. 711 - 714
(2007/10/03)
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- Synthesis of apicidin
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Tetrapeptide containing L-2-amino-8-protected hydroxydecanoic acid, L-N-O-methyltryptophan, L-isoleucine and D-pipecolinic acid was cyclized with pentafluorophenyl diphenylphosphinate. The cyclic tetrapeptide was deprotected and oxidized to apicidin [cyclo-(N-O-methyl-L-Trp-L-Ile-D-Pip-L-2-amino-8-oxo-decanoyl)].
- Kuriyama, Wataru,Kitahara, Takeshi
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- Facile chemoselective synthesis of dehydroalanine-containing peptides.
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Useful methodology is described for the synthesis of dehydroalanine residues (II) within peptides. The unnatural amino acid (Se)-phenylselenocysteine (I) can be incorporated into growing peptide chains via standard peptide synthesis procedures. Subsequent
- Okeley,Zhu,van Der Donk
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p. 3603 - 3606
(2007/10/03)
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- The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: Rational modifications imparting PP1 selectivity
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Based on the results from previously reported molecular modeling analyses of the interactions between the inhibitor microcystin and the serine-threonine protein phosphatases 1 and 2A, we have designed analogues of microcystin LA with structural modifications intended to impart PP1 selectivity. The synthesis of several first generation analogues followed by inhibition assays revealed that all three are PP1-selective, as predicted. Although the observed selectivities are modest, one of the designed analogues is more selective for PP1 than any known small molecule inhibitor. Copyright (C) 1999 Elsevier Science Ltd.
- Aggen, James B.,Humphrey, John M.,Gauss, Carla-Maria,Huang, Hsien-Bin,Nairn, Angus C.,Chamberlin, A. Richard
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p. 543 - 564
(2007/10/03)
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- Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7- quinoxaline-2,3-diones: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor agonists and antagonists
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Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have been found to antagonize specific binding and functional responses to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid. Although a variety of studies have an
- Sun, Guoping,Uretsky, Norman J.,Wallace, Lane J.,Shams, Gamal,Weinstein, David M.,Miller, Duane D.
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p. 4430 - 4438
(2007/10/03)
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- Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase
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The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described.Compound 3, wherein a β-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 μM) and mevalonate kinase (I50(MK) = >200 μM).A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken.Both the carboxylic and phosphonic acid groups of the β-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 μM).The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 μM), substitution by a dodecyl fragment (14, I50 = 9 μM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 μM).Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 μM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM).FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.
- Patel, Dinesh V.,Schmidt, Robert J.,Biller, Scott A.,Gordon, Eric M.,Robinson, Simon S.,Manne, Veeraswamy
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p. 2906 - 2921
(2007/10/02)
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- Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor
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2,2-Dimethyl-3-(2'-hydroxypropyl)-5-carboxy-Δ3-1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C=N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C=N → Enz-O-C-NH. Compound 1 also contains additional substituents that are designed to position the O-H and C=N groups relative to one another in the enzyme-substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of 1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3-hexanone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcohol established, by reaction of the R- and S-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. The R alcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. The R and S enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S enantiomers of 3 to yield each of the stereoisomers of the chemically unstable 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8R isomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed. 2,2-Dimethyl-3-(2′-hydroxypropyl)-5-carboxy- Δ3-1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C = N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C = N → Enz-O-C-NH. Compound 1 also contains additional substituents that are designed to position the O-H and C = N groups relative to one another in the enzyme-substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of 1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3-hex anone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcohol established, by reaction of the R- and S-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. The R alcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. The R and S enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S enantiomers of 3 to yield each of the stereoisomers of the chemically unstable 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8S isomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed.
- Wolfe,Zhang,Johnston,Kim
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p. 1066 - 1075
(2007/10/02)
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- Interactive design and synthesis of a novel antibacterial agent
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β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e., fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat 'fit,' and ab initio molecular orbital calculations to treat 'reactivity,' leads to the idea that the carboxyl group (G1) and the amide N-H (G2) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme-substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure-reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (-ΔE > 10 kcal/mol). Accordingly, structures containing a G1 and a G2 separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D- and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.
- Wolfe,Jin,Yang,Kim,McEachern
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p. 1051 - 1065
(2007/10/02)
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- Syntheses of optically pure α-amino acids from 3-amino-2-oxetanone salts
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A process for the preparation of optically pure α-amino acids comprising the nucleophilic ring-opening of 3-amino-2-oxetanone salts. N-Protected serine β-lactones are deprotected to form heretofore unknown 3-amino-2-oxetanone and its corresponding salts. In turn these previously unknown 3-amino-2-oxetanone salts may be used in the synthesis of other novel or rare stereochemically-pure free amino acids.
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- Polymer-Supported Alkyl Azodicarboxylates for Mitsunobu Reactions
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Reaction of hydroxymethyl polystyrene 1 (1percent cross-linked) with phosgene followed by methyl carbazate gives methyl hydrazodicarboxylate polystyrene resin 2, which upon oxidation (e.g., N-bromosuccinimide/pyridine or chlorine/water) affords methyl azodicarboxylate polystyrene resin 3.This substitute for soluble dialkyl azodicarboxylates functions well as an easily separable (insoluble) and nonexplosive reagent in Mitsunobu reactions.In the cases examined, yields of hydroxyl replacement by oxygen, nitrogen, and carbon nucleophiles are comparable, product purification isfacilitated, and the polymeric reagent can be reoxidized and reused at least five times without loss of activity.
- Arnold, Lee D.,Assil, Hanaa I.,Vederas, John C.
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p. 3973 - 3976
(2007/10/02)
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