- Macrocyclic Transmembrane Anion Transporters via a One-Pot Condensation Reaction
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Synthetic chloride transporters are potential therapeutic agents for cystic fibrosis and cancer. Reported herein are macrocyclic transmembrane chloride transporters prepared by a one-pot condensation reaction. The most efficient macrocycle possesses a fine balance of hydrophobicity for membrane permeation and hydrophilicity for ion recognition. The macrocycle transports chloride ions by forming channels in the membrane. Hydrogen bonds and anion-πinteractions assist chloride transport.
- Saha, Parichita,Madhavan, Nandita
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- SYNTHESIS OF A MODEL DEPSIPEPTIDE SEGMENT OF LUZOPEPTINS (BBM 928), POTENT ANTITUMOR AND ANTIRETROVIRAL ANTIBIOTICS
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A modified Rapoport procedure was used to synthesize a tripeptide containing N-methyl-3-hydroxyvaline, an unusual aminoacid found in Luzopeptins.
- Ciufolini, Marco A.,Swaminathan, Shankar
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- Synthesis, photophysical properties of triazolyl-donor/acceptor chromophores decorated unnatural amino acids: Incorporation of a pair into Leu-enkephalin peptide and application of triazolylperylene amino acid in sensing BSA
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The research in the field of design and synthesis of unnatural amino acids is growing at a fast space for the increasing demand of proteins of potential therapeutics and many other diversified novel functional applications. Thus, we report herein the design and synthesis of microenvironment sensitive fluorescent triazolyl unnatural amino acids (UNAA) decorated with donor and/or acceptor aromatic chromophores via click chemistry. The synthesized fluorescent amino acids show interesting solvatochromic characteristic and/or intramolecular charge transfer (ICT) feature as is revealed from the UV–visible, fluorescence photophysical properties and DFT/TDDFT calculation. HOMO–LUMO distribution shows that the emissive states of some of the amino acids are characterized with more significant electron redistribution between the triazolyl moiety and the aromatic chromophores linked to it leading to modulated emission property. A pair of donor–acceptor amino acid shows interesting photophysical interaction property indicating a FRET quenching event. Furthermore, one of the amino acid, triazolyl-perylene amino acid, has been exploited for studying interaction with BSA and found that it is able to sense BSA with an enhancement of fluorescence intensity. Finally, we incorporated a pair of donor/acceptor amino acids into a Leu-enkephalin analogue pentapeptide which was found to adopt predominantly type II β-turn conformation. We envisage that our investigation is of importance for the development of new fluorescent donor–acceptor unnatural amino acids a pair of which can be exploited for generating fluorescent peptidomimetic probe of interesting photophysical property for applications in studying peptide–protein interaction.
- Bag, Subhendu Sekhar,Jana, Subhashis,Pradhan, Manoj Kumar
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- PRODRUGS OF ABIRATERONE
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The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers, or pharmaceutically acceptable salt(s) thereof as prodrugs of abiraterone. The present invention also describes method of making such compounds, pharmaceutical compositions comprising such compounds and the use of the compounds of formula (I).
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Page/Page column 20-21
(2021/05/29)
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- Synthesis and Biological Evaluation of CF3Se-Substituted α-Amino Acid Derivatives
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Several CF3Se-substituted α-amino acid derivatives, such as (R)-2-amino-3-((trifluoromethyl)selanyl)propanoates (5 a/6 a), (S)-2-amino-4-((trifluoromethyl)selanyl)butanoates (5 b/6 b), (2R,3R)-2-amino-3-((trifluoromethyl)selanyl)butanoates (5 c/6 c), (R)-2-((S)-2-amino-3-phenylpropanamido)-3-((trifluoromethyl)selanyl)propanoates (11 a/12 a), and (R)-2-(2-aminoacetamido)-3-((trifluoromethyl)selanyl)propanoates (11 b/12 b), were readily synthesized from natural amino acids and [Me4N][SeCF3]. The primary in vitro cytotoxicity assays revealed that compounds 6 a, 11 a and 12 a were more effective cell growth inhibitors than the other tested CF3Se-substituted derivatives towards MCF-7, HCT116, and SK-OV-3 cells, with their IC50 values being less than 10 μM for MCF-7 and HCT116 cells. This study indicated the potentials of CF3Se moiety as a pharmaceutically relevant group in the design and synthesis of novel biologically active molecules.
- Han, Zhou-Zhou,Dong, Tao,Ming, Xiao-Xia,Kuang, Fu,Zhang, Cheng-Pan
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supporting information
p. 3177 - 3180
(2021/07/28)
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- Azidosphinganine enables metabolic labeling and detection of sphingolipidde novosynthesis
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Here were report the combination of biocompatible click chemistry of ω-azidosphinganine with fluorescence microscopy and mass spectrometry as a powerful tool to elaborate the sphingolipid metabolism. The azide probe was efficiently synthesized over 13 steps starting froml-serine in an overall yield of 20% and was used for live-cell fluorescence imaging of the endoplasmic reticulum in living cells by bioorthogonal click reaction with a DBCO-labeled fluorophore revealing that the incorporated analogue is mainly localized in the endoplasmic membrane like the endogenous species. A LC-MS(/MS)-based microsomalin vitroassay confirmed that ω-azidosphinganine mimics the natural species enabling the identification and analysis of metabolic breakdown products of sphinganine as a key starting intermediate in the complex sphingolipid biosynthetic pathways. Furthermore, the sphinganine-fluorophore conjugate after click reaction was enzymatically tolerated to form its dihydroceramide and ceramide metabolites. Thus, ω-azidosphinganine represents a useful biofunctional tool for metabolic investigations both byin vivofluorescence imaging of the sphingolipid subcellular localization in the ER and byin vitrohigh-resolution mass spectrometry analysis. This should reveal novel insights of the molecular mechanisms sphingolipids and their processing enzymes havee.g.in infection.
- Fink, Julian,Schumacher, Fabian,Schlegel, Jan,Stenzel, Philipp,Wigger, Dominik,Sauer, Markus,Kleuser, Burkhard,Seibel, Jürgen
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supporting information
p. 2203 - 2212
(2021/03/24)
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- Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites
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There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet–Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds’ bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.
- Cockram, Peter E.,Slawin, Alexandra M. Z.,Smith, Terry K.,Turner, Callum A.
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supporting information
(2022/01/11)
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- One-Step Azolation Strategy for Site- and Chemo-Selective Labeling of Proteins with Mass-Sensitive Probes
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The chemical modification of proteins in a site-selective manner leads to many advances in various scientific fields. The major challenges with conventional N-terminal bioconjugation techniques are the lack of universal sequence compatibility and poor mass-detection sensitivity of the resulting bioconjugates. This approach efficiently analyzes proteolytic fragments and native proteins in a complex mixture. Multiple chemical steps are usually required for the site-selective synthesis of bioconjugates with enhanced mass-detection sensitivity. We present a single-step, versatile strategy for the selective modification of protein N-termini with mass boosters. The chemical tag enhances the peptide detection by multiple orders thus leading to the unambiguous analysis of the resulting bioconjugates. We demonstrate that tagging proteolytic fragments with mass sensitivity probes in a complex mixture improves the detection of resulting bioconjugates.
- Tang, Kuei C.,Raj, Monika
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supporting information
p. 1797 - 1805
(2020/12/02)
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- ?-LACTAMASE INHIBITOR AND USE THEREOF
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Provided are a β-lactamase inhibitor of formula (I), or an ester, a stereoisomer or a pharmaceutically acceptable salt thereof, and a method of preparing the same. Further provided is a pharmaceutical composition comprising the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or pharmaceutically acceptable salt thereof. In addition, the present invention relates to a method for treating diseases caused by bacterial infection, which comprises administering the β-lactamase inhibitor of formula (I), or the ester, the stereoisomer or the pharmaceutically acceptable salt thereof to a patient or a subject in need.
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Paragraph 0247; 0248
(2020/12/10)
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- Liposomal FRET Assay Identifies Potent Drug-Like Inhibitors of the Ceramide Transport Protein (CERT)
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Ceramide transfer protein (CERT) mediates non-vesicular transfer of ceramide from endoplasmic reticulum to Golgi apparatus and thus catalyzes the rate-limiting step of sphingomyelin biosynthesis. Usually, CERT ligands are evaluated in tedious binding assays or non-homogenous transfer assays using radiolabeled ceramides. Herein, a facile and sensitive assay for CERT, based on F?rster resonance energy transfer (FRET), is presented. To this end, we mixed donor and acceptor vesicles, each containing a different fluorescent ceramide species. By CERT-mediated transfer of fluorescent ceramide, a FRET system was established, which allows readout in 96-well plate format, despite the high hydrophobicity of the components. Screening of a 2 000 compound library resulted in two new potent CERT inhibitors. One is approved for use in humans and one is approved for use in animals. Evaluation of cellular activity by quantitative mass spectrometry and confocal microscopy showed inhibition of ceramide trafficking and sphingomyelin biosynthesis.
- Aglar, ?znur,Arenz, Christoph,Banhart, Sebastian,Cong, Xiaojing,Hamdo, Housam H.,Heuer, Dagmar,Kleuser, Burkhard,M?ller, Heiko M.,Saied, Essa M.,Samaha, Doaa,Schumacher, Fabian
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supporting information
p. 16616 - 16621
(2020/11/30)
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- HETEROCYCLIC AMIDES AS KINASE INHIBITORS FOR USE IN THE TREATMENT CANCER
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Disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg. Also disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg, and administering to the human a PD1 antagonist thereof at a dose of about 200 mg.
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Page/Page column 100; 102; 103
(2020/03/24)
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- Design, Synthesis, and Conformation-Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents
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By carrying out structural modifications based on the bicyclic peptide structure of echinomycin, we successfully synthesized various powerful antitumor derivatives. The ring conformation in the obtained compounds was restricted by cross-linking with an unnatural bond. The prepared derivatives were demonstrated to strongly suppress the hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia induction of HIF-1 protein expression. Particularly, alkene-bridged derivative 12 exhibited remarkably potent cytotoxicity (IC50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition (IC50 = 0.09 nM), which considerably exceeded those of echinomycin. Conformational analyses and molecular modeling studies revealed that the biological activities were enhanced following restriction of the conformation by cross-linking through a metabolically stable and rigid bridge bond. In addition, we proposed a new globular conformation stabilized by intramolecular πstacking that can contribute to the biological effects of bicyclic depsipeptides. The developments presented in the current study serve as a useful guide to expand the chemical space of peptides in drug discovery.
- Koike, Kota,Nagano, Masanobu,Ebihara, Masahiro,Hirayama, Tasuku,Tsuji, Mieko,Suga, Hiroaki,Nagasawa, Hideko
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p. 4022 - 4046
(2020/06/08)
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- High-efficiency preparation method of D-dencichine
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The invention relates to a high-efficiency synthesis method of a hemostasis compound D-dencichine, comprising the following steps: firstly enabling D-serine to react with di-tert-butyl dicarbonate ester to generate Boc-D-serine, then generating Gabriel reaction with hydroxy of methylsulfonyl chloride activated Boc-D--serine to obtain N-alpha-Boc-D-alpha, beta-diaminopro, finally condensing with oxalate mono-methyl ester sylvite then performing hydrolytic acidification to obtain a dencichine crude product, and purifying to obtain a dencichine competitive product, with the product content reaching more than 99.8%. Compared with existing D-dencichine synthesis methods, the reaction condition is more mild, the operation is simple and convenient, the material cost is relatively low, and the hemostasis compound D-dencichine is environment-friendly, is suitable for industrial production, and solves the problem of resource for later development of clinical trial of D-dencichine.
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Paragraph 0016; 0017
(2019/01/21)
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- Trifluoromethyl selenoamino acid derivative and preparation method thereof
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The invention discloses a trifluoromethyl selenoamino acid derivative and a preparation method thereof. The preparation method comprises the following steps: by taking amino acid as an initial raw material, performing an N-Boc protection reaction with an N-Boc protection reagent so as to obtain amino N-Boc protected amino acid; performing an esterification reaction on the amino N-Boc protected amino acid with an esterification reagent so as to obtain an esterification product; performing a sulfonylation reaction on the esterification product with a sulfonylation reagent so as to obtain a sulfonylation product; and performing a trifluoromethyl selenium formation reaction on the sulfonylation product with a trifluoromethyl selenium salt, so as to obtain the amino N-Boc protected trifluoromethyl selenoamino acid derivative. The reaction is not only simple and convenient in operation, mild in condition, high in yield and good in functional group resistance, but also cheap in raw material,easy in raw material obtaining, and a very practical method is provided for synthesizing the trifluoromethyl selenoamino acid derivative.
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Paragraph 0068-0070
(2019/11/28)
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- L-serine linked dihydroartemisinin-fluoroquinolone conjugate and intermediate thereof, preparation methods of L-serine linked dihydroartemisinin-fluoroquinolone conjugate and intermediate thereof, and uses of L-serine linked dihydroartemisinin-fluoroquinolone conjugate
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The invention discloses an L-serine linked dihydroartemisinin-fluoroquinolone conjugate represented by a formula I, an intermediate represented by a formula II, preparation methods of the compounds represented by the formula I and the formula II, and uses of the compound represented by the formula I in preparation of anti-Mycobacterium tuberculosis drugs or/and blood lipid lowering drugs.
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Paragraph 0054-0057
(2019/11/29)
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- 3-substituted-1,5-benzodiazepine compound and pharmaceutical application thereof
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The invention belongs to the technical field of medicine, and relates to a 3-substituted-1,5-benzodiazepine compound with a general molecular formula of a formula I and application of the 3-substituted-1,5-benzodiazepine compound to medicine. The 3-substituted-1,5-benzodiazepine compound can selectively inhibit the activity of glycogen synthase kinase-3beta (GSK 3beta) and can be used for the preparation of the medicine for preventing and/or treating diseases with abnormal pathological characteristics of the GSK 3beta, wherein the diseases includes cancer, neurological diseases, metabolic syndromes and the like. (Please see the specification for the formula.)
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Paragraph 0116; 0118-0120
(2019/11/20)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders as well as other disorders.
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Page/Page column 29
(2019/08/26)
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- Rhamnolipid inspired lipopeptides effective in preventing adhesion and biofilm formation of Candida albicans
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Rhamnolipids are biodegradable low toxic biosurfactants which exert antimicrobial and anti-biofilm properties. They have attracted much attention recently due to potential applications in areas of bioremediation, therapeutics, cosmetics and agriculture, however, the full potential of these versatile molecules is yet to be explored. Based on the facts that many naturally occurring lipopeptides are potent antimicrobials, our study aimed to explore the potential of replacing rhamnose in rhamnolipids with amino acids thus creating lipopeptides that would mimic or enhance properties of the parent molecule. This would allow not only for more economical and greener production but also, due to the availability of structurally different amino acids, facile manipulation of physico-chemical and biological properties. Our synthetic efforts produced a library of 43 lipopeptides revealing biologically more potent molecules. The structural changes significantly increased, in particular, anti-biofilm properties against Candida albicans, although surface activity of the parent molecule was almost completely abolished. Our findings show that the most active compounds are leucine derivatives of 3-hydroxy acids containing benzylic ester functionality. The SAR study demonstrated a further increase in activity with aliphatic chain elongation. The most promising lipopeptides 15, 23 and 36 at 12.5 μg/mL concentration allowed only 14.3%, 5.1% and 11.2% of biofilm formation, respectively after 24 h. These compounds inhibit biofilm formation by preventing adhesion of C. albicans to abiotic and biotic surfaces.
- Jovanovic, Milos,Radivojevic, Jelena,O'Connor, Kevin,Blagojevic, Stevan,Begovic, Biljana,Lukic, Vera,Nikodinovic-Runic, Jasmina,Savic, Vladimir
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supporting information
p. 209 - 217
(2019/03/23)
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- Posaconazole derivative, pharmaceutical composition and use thereof
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The present disclosure provides a posaconazole derivative, a pharmaceutical composition and use thereof, which specifically include a compound represented by the following formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof: The compounds of the present disclosure have strong antifungal activity, high safety, and good water solubility, without the need for the addition of a cosolvent (such as hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and the like) with potential safety risks. Furthermore, the formulation process of the compound could have less difficulty and less cost, and therefore can be used to prepare improved antifungal drugs.
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Page/Page column 221-224
(2020/01/22)
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- Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles
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The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.
- Zhang, En,Bai, Peng-Yan,Cui, De-Yun,Chu, Wen-Chao,Hua, Yong-Gang,Liu, Qin,Yin, Hai-Yang,Zhang, Yong-Jie,Qin, Shangshang,Liu, Hong-Min
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p. 1489 - 1509
(2017/11/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LACOSAMIDE
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The present invention relates to an improved process for the synthesis of (R)- Lacosamide in which free base of O-methyl-N-benzyl-D-Serinamide is not isolated before acylation. The process avoids the use of column chromatography and chiral resolution for the preparation of different stages of Lacosamide.
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Page/Page column 16-17
(2018/04/17)
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- Total Synthesis of Plusbacin A3 and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction
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Full details of our synthetic studies toward plusbacin A3 (1), which is a depsipeptide with antibacterial activity, and its dideoxy derivative are described. To establish an efficient synthetic route of 1, a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) was used to construct trans-Pro(3-OH) in a small number of steps. Two strategies were investigated toward the total synthesis. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a macrolactonization at the final stage of the synthesis. The JU-3CR using alkyl isocyanides in 1,1,1,3,3,3-hexafluoroisopropanol provided the trans products, and the coupling of the fragments to prepare the macrocyclization precursor proceeded smoothly. However, attempts toward the macrolactonization did not provide the desired product. Then, the second strategy that included esterification in an initial stage was investigated. Methods for constructing trans-Pro(3-OH) were examined using a convertible isocyanide, which could be converted to a carboxylic acid required for the following amidation. Ester bond formation was achieved through an intermolecular coupling using a hydroxyl-Asp derivative and the corresponding alcohol, and the amidation afforded a linear depsipeptide. The macrolactamization of the linear peptide gave the cyclic depsipeptide, and then the global deprotection accomplished the total synthesis of 1 and its dideoxy derivative.
- Katsuyama, Akira,Yakushiji, Fumika,Ichikawa, Satoshi
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p. 7085 - 7101
(2018/07/15)
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- In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3-Amino-1-carboxymethyl-β-lactams as Inhibitors of Penicillin-Binding Proteins of Resistant Bacteria
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As a complement to the renowned bicyclic β-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten-step synthesis of eleven nocardicin-like enantiomerically pure 2-{3-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-2-oxoazetidin-1-yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-β-lactams to inhibit penicillin-binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α-benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β-lactamase classes was observed, while weak inhibition of class C β-lactamase P99 was demonstrated.
- Decuyper, Lena,Deketelaere, Sari,Vanparys, Lore,Juki?, Marko,Sosi?, Izidor,Sauvage, Eric,Amoroso, Ana Maria,Verlaine, Olivier,Joris, Bernard,Gobec, Stanislav,D'hooghe, Matthias
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supporting information
p. 15254 - 15266
(2018/09/25)
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- HETEROCYCLIC AMIDES AS KINASE INHIBITORS
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Disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent for use in the treatment of a RIP1 kinase mediated disease or disorder; particularly disclosed is a combination of a RIP1 kinase inhibitor compound and at least one other therapeutically active agent, wherein the at least one other therapeutically active agent is an immuno-modulator, for use in the treatment of cancer.
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Page/Page column 108; 109
(2018/09/26)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 81
(2018/03/09)
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- Synthesis of a cisplatin derivative from lithocholic acid
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A new steroidal-platinum(II) hybrid compound was synthesized using a simple and efficient methodology. The synthesis was performed by a convergent approach with cross metathesis (CM) as a key step. An olefin derived from lithocholic acid and a vinyl substituted ethylenediamine derived from L-serine were used as chiral building blocks, which were combined in the CM step. The most important advantage of this method was the utilization of L-serine as a cheap, stereoisomerically pure substrate. A steroid with a diamino system in the side chain was subjected to reaction with potassium tetrachloroplatinate to obtain the target platinum(II) complex. Attempts to synthesize similar diamine systems using the asymmetric Strecker reaction were unsuccessful.
- Hryniewicka, Agnieszka,?otowski, Zenon,Seroka, Barbara,Witkowski, Stanis?aw,Morzycki, Jacek W.
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supporting information
p. 5392 - 5398
(2018/02/12)
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- Improved preparation method of modified lacosamide
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The invention discloses an improved preparation method of modified lacosamide, which is simple to operate, high in chiral purity and low in cost. According to the improved preparation method, in step 1, amidation is carried out on amino by utilizing di-tert butyl dicarbonate (Boc for short), wherein conditions are moderate and the chiral purity is high and at least reaches 90 percent or more; in step 4, high-selectivity dimethyl sulfate is used as a methylation reagent; the cost is low and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application. The improved preparation method has the most important innovation points that the Boc is used as an N-protection agent and a Boc protecting group can be simply and conveniently removed by adding acid and a hydrogenation removal means does not need to be used. Secondly, the low-price dimethyl sulfate is used for carrying out methylation and the conditions are moderate; the methylation yield is high and the improved preparation method is more suitable for large-scale application.
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Paragraph 0036-0039
(2017/08/31)
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- Optimized syntheses of Fmoc azido amino acids for the preparation of azidopeptides
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The rise of CuI-catalyzed click chemistry has initiated an increased demand for azido and alkyne derivatives of amino acid as precursors for the synthesis of clicked peptides. However, the use of azido and alkyne amino acids in peptide chemistry is complicated by their high cost. For this reason, we investigated the possibility of the in-house preparation of a set of five Fmoc azido amino acids: β-azido l-alanine and d-alanine, γ-azido l-homoalanine, δ-azido l-ornithine and ω-azido l-lysine. We investigated several reaction pathways described in the literature, suggested several improvements and proposed several alternative routes for the synthesis of these compounds in high purity. Here, we demonstrate that multigram quantities of these Fmoc azido amino acids can be prepared within a week or two and at user-friendly costs. We also incorporated these azido amino acids into several model tripeptides, and we observed the formation of a new elimination product of the azido moiety upon conditions of prolonged couplings with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/DIPEA. We hope that our detailed synthetic protocols will inspire some peptide chemists to prepare these Fmoc azido acids in their laboratories and will assist them in avoiding the too extensive costs of azidopeptide syntheses. Experimental procedures and/or analytical data for compounds 3–5, 20, 25, 26, 30 and 43–47 are provided in the supporting information.
- Pícha, Jan,Budě?ínsky, Milo?,Machá?ková, Kate?ina,Collinsová, Michaela,Jirá?ek, Ji?í
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p. 202 - 214
(2017/04/06)
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- Hierarchical supramolecular hydrogels: Self-assembly by peptides and photo-controlled release: Via host-guest interaction
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A hierarchical supramolecular hydrogel was self-assembled from a Fmoc-RGDS tetrapeptide and showed photo-controlled release directed by host-guest interaction. Multiple payloads, including vesicles, were successively released from a single peptide hydrogel.
- Chu, Chih-Wei,Ravoo, Bart Jan
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supporting information
p. 12450 - 12453
(2017/11/22)
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- Protecting group free synthesis of glycosyl thiols from reducing sugars in water; application to the production of N-glycan glycoconjugates
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Glycosyl thiols may be accessed from the corresponding reducing sugars in water without recourse to any sugar projecting groups by way of a DMC mediated reaction with thioacetic acid in the presence of base, and hydrolysis of the anomeric thioacetate. Glycosyl thiols produced by this method may be used to access glycoconjugates, such as glycopeptides by use of the thiol-ene click reaction.
- Alexander,Lim,Amso,Brimble,Fairbanks
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supporting information
p. 2152 - 2156
(2017/03/20)
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- Amplification of a FRET Probe by Lipid–Water Partition for the Detection of Acid Sphingomyelinase in Live Cells
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Real-time monitoring of acid sphingomyelinase (ASM) activity is crucial for investigating its role in lipid-mediated signaling processes. In this study, we synthesized fluorescent phosphosphingolipids capable of FRET by phosphorodichloridate chemistry. These sphingomyelin analogues are substrates for recombinant human ASM and can be used to monitor ASM activity by fluorescence spectroscopy. Incubation with cell lysates from wild-type and knock-out mice further confirmed probe cleavage to be exclusive to ASM. We also systematically exploited the environmental sensitivity of the fluorophores to achieve significant increases in responsiveness. This concept may be transferred to other lipid probes in the future. The ASM activity in live cells was imaged by two-photon-excitation microscopy.
- Pinkert, Thomas,Furkert, David,Korte, Thomas,Herrmann, Andreas,Arenz, Christoph
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supporting information
p. 2790 - 2794
(2017/02/26)
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- Process for preparation of optically pure N-substituted-3-methoxypropionic acid derivatives
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A method of producing optically pure N-substituted-3-methoxy propionic acid is provided, which includes the steps of: reacting N-substituted-3-methoxy propionic acid represented by formula (III): with a chiral amine in a solvent to obtain a diastereomeric salt represented by formula (IV): subjecting the diastereomeric salt to a sequential washing process to obtain the optically pure N-substituted-3-methoxy propionic acid represented by one of formulae (Ia) and (Ib): wherein R1 is selected from the group consisting of C1-5 alkyl, C1-6 alkoxy and C6-10 aryloxy group, and R2 is selected from the group consisting of C2-5 alkyl, C6-8 cycloalkyl and C6-10 aryl.
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Page/Page column 5
(2017/08/26)
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- Dialkyl cationic amphiphilic antibacterial peptide analogue with antibacterial activity and preparation method thereof
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The invention belongs to the field of medicinal chemistry, and discloses a dialkyl cationic amphiphilic antibacterial peptide analogue with antibacterial activity and a synthesis method thereof. Through four-step reaction, a target product can be simply and fast obtained. A major structure is shown as the accompanying drawing. In-vitro antibacterial activity experiments prove that the most compounds in the series show good antibacterial effects on staphylococcus aureus and escherichia coli; partial compounds show excellent antibacterial activity on super bacteria including MRSA (methicillin-resistance staphylococcus aureus), VRE (vancomycin-resistant enterococcus) and CRE (carbapenemase enterobacteriaceae). In-vitro red cell toxicity experiments also show the series of compounds have low red cell toxicity, so that the series of compounds are hopeful to be used as novel antibacterial candidate medicine. The formulas are shown in the description.
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Paragraph 0068
(2017/09/01)
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- PROCESS FOR PREPARATION OF SACUBUTRIL INTERMEDIATE
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The present application relates to a process for preparation of tert-butyl (R)-(1-([1,1'-biphenyl]-4- yl)-3-hydroxypropan-2-yl)carbamate (IA). The compound of formula (IA) may be used as an intermediate for the preparation of sacubitril.
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Page/Page column 24
(2017/12/29)
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- New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
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A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
- Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
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supporting information
p. 2127 - 2132
(2017/10/31)
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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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- A rakow amide preparation method
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A preparing process of lacosamide is disclosed. D-serine is adopted as an initial raw material. The method includes: performing amino protection, performing methylation, condensing with benzylamine under a condition of existence of a carboxyl activator, removing an amino protection group, and performing amidation to obtain the lacosamide. The total yield is higher than 66%. The method is high in yield, simple and convenient to operate, high in product purity and especially suitable for industrial production.
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Paragraph 0095; 0096
(2016/10/17)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 732; 733
(2016/04/10)
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- Improved synthetic routes to the selenocysteine derivatives useful for Boc-based peptide synthesis with benzylic protection on the selenium atom
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Selenocysteine (Sec) derivatives, i.e., Boc-Sec(MBn)-OH (1) and Boc-Sec(MPM)-OH (2), which are useful for chemical synthesis of selenopeptides, were obtained from L-serine in five steps with total yields of 73% and 74%, respectively. The enantiomeric excesses were confirmed to be >99% e.e. by optical resolution using a chiral column on HPLC. On the other hand, for the case of a Fmoc-protected Sec derivative, i.e., Fmoc-Sec(MPM)-OH, similar reactions resulted in low yields and partial racemization taking place. [PRESENTED EQUATION]
- Shimodaira, Shingo,Iwaoka, Michio
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p. 260 - 271
(2017/03/09)
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- Total synthesis of the azolemycins
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The first total syntheses of newly isolated polyazole natural products azolemycins A-D, along with the synthesis of the tetra-oxazole non-natural analogue, are described.
- Anderson, Zoe J.,Fox, David J.
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supporting information
p. 1450 - 1454
(2016/02/03)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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- LYSOPHOSPHATIDYLSERINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a lysophosphatidylserine derivative or salt thereof. SOLUTION: The present invention provides a lysophosphatidylserine derivative or salt thereof, or a pharmaceutical composition or lysophosphatidylserine receptor function modulator including the compound or salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0265-0266
(2016/10/07)
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- LYSOPHOSPHATIDYLSERINE DERIVATIVE COMPRISING FATTY ACID SURROGATE
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PROBLEM TO BE SOLVED: To provide a lysophosphatidylserine derivative to serve as a lysophosphatidylserine receptor function modulator or salt thereof, and a fatty acid surrogate which can be used as a synthetic intermediate of these compounds. SOLUTION: The present invention relates to, for example, a lysophosphatidylserine derivative of the following formula that is obtained by the condensation of the synthetic intermediate 3-(2-((3-(o-tolyloxy)benzil)oxy)phenyl)propanoic acid induced from o-cresol with a corresponding serine phosphoester compound having a hydroxy group. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0354
(2016/10/08)
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- Biomimetic Synthesis of Urukthapelstatin A by Aza-Wittig Ring Contraction
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Marine bacteria produce highly cytotoxic polyheterocyclic cyclopeptide natural products by ribosomal peptide biosynthesis. Among them, urukthapelstatin A features a chain of five 2,4′-connected azole rings within a cyclo-octapeptide framework. We report a novel synthesis design that uses only α-amino acids as starting materials that leads to an efficient and stereoselective total synthesis of urukthapelstatin A. Kinetically favored macro-thiolactonization and high-yielding aza-Wittig heterocyclization to contract the macrocycle were crucial for success. These investigations additionally uncovered the unsuspected configurational lability of the embedded enamide substructure in solution.
- Schwenk, Sebastian,Ronco, Cyril,Oberheide, Ansgar,Arndt, Hans-Dieter
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p. 4795 - 4799
(2016/10/13)
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- SAR and structural analysis of siderophore-conjugated monocarbam inhibitors of pseudomonas aeruginosa PBP3
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A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design.
- Murphy-Benenato, Kerry E.,Dangel, Brian,Davis, Hajnalka E.,Durand-Réville, Thomas F.,Ferguson, Andrew D.,Gao, Ning,Jahi?, Haris,Mueller, John P.,Manyak, Erika L.,Quiroga, Olga,Rooney, Michael,Sha, Li,Sylvester, Mark,Wu, Frank,Zambrowski, Mark,Zhao, Shannon X.
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supporting information
p. 537 - 542
(2015/05/27)
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- Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
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Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
- Ikubo, Masaya,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Sayama, Misa,Otani, Yuko,Uwamizu, Akiharu,Suzuki, Keisuke,Kishi, Takayuki,Shuto, Akira,Ishiguro, Jun,Okudaira, Michiyo,Kano, Kuniyuki,Makide, Kumiko,Aoki, Junken,Ohwada, Tomohiko
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supporting information
p. 4204 - 4219
(2015/06/08)
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- Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid
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Several strategies aimed to "freeze" natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson's and Alzheimer's and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3-C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction.
- Bechi, Beatrice,Amantini, David,Tintori, Cristina,Botta, Maurizio,Di Fabio, Romano
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p. 1114 - 1120
(2014/06/09)
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- Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in Vitro cytotoxic evaluation
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We have previously reported the discovery of cytotoxic and pro-Apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3- oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-Apoptotic potential.
- Andrade, Saulo F.,Campos, Edmar F.S.,Teixeira, Claudia S.,Bandeira, Cristiano C.,Lavorato, Stefania N.,Romeiro, Nelilma C.,Bertollo, Caryne M.,Oliveira, M?nica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
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p. 609 - 618
(2014/11/07)
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- NOVEL PROCESS FOR THE PREPARATION OF (R)-N-BENZYL-2-ACETAMIDO-3-METHOXYPROPIONAMIDE
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The invention is a novel process for the preparation of lacosamide by employing novel intermediates of formula III and IV:
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Paragraph 0042
(2014/11/11)
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- PROCESS FOR THE PREPARATION OF LACOSAMIDE USING NOVEL INTERMEDIATES
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The present invention provides an improved and commercial process for the preparation of Lacosamide having formula (I). Further, the present invention also provides the novel intermediate compounds of formula (VI) and (VII) and their process for the preparation. Present process utilizes compound of formula (VI) and (VI)I as key novel intermediates for the preparation of Lacosamide.
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Page/Page column 11-12
(2014/10/15)
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- Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain
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Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β3- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI = 5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
- Sinha, Manish,Dola, Vasanth R.,Agarwal, Pooja,Srivastava, Kumkum,Haq, Wahajul,Puri, Sunil K.,Katti, Seturam B.
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p. 3573 - 3586
(2014/07/07)
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