- Optimization of globomycin analogs as novel gram-negative antibiotics
-
Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.
- Braun, Marie-Gabrielle,Burdick, Daniel J.,Castanedo, Georgette M.,Chen, Yi-Chen,Cheng, Yun-Xing,Cheong, Jonathan,Daniels, Blake,Deshmukh, Gauri,Fu, Yuhong,Garland, Keira,Gibbons, Paul,Gloor, Susan L.,Hanan, Emily J.,Hua, Rongbao,Kapadia, Sharookh B.,Labadie, Sharada,Liu, Xiongcai,Pantua, Homer,Pastor, Richard,Stivala, Craig,Xu, Min,Xu, Yiming,Zheng, Hao
-
supporting information
(2020/08/13)
-
- CYCLIC PEPTIDE ANTIBIOTICS
-
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
- -
-
Paragraph 00171
(2020/09/27)
-
- KCNT1 INHIBITORS AND METHODS OF USE
-
The present invention is directed to, in part, compounds and compositions useful for preventing and/or treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene (e.g., KCNT1). Methods of treating a neurological disease or disorder, a disease or condition relating to excessive neuronal excitability, and/or a gain-of-function mutation in a gene such as KCNT1 are also provided herein.
- -
-
Paragraph 000579
(2020/11/23)
-
- CYCLIC PEPTIDE ANTIBIOTICS
-
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of lipoprotein signal peptidase II (LspA), a key protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
- -
-
Paragraph 00300
(2019/04/11)
-
- Synthesis of the Siderophore Coelichelin and Its Utility as a Probe in the Study of Bacterial Metal Sensing and Response
-
A convergent total synthesis of the siderophore coelichelin is described. The synthetic route also provided access to acetyl coelichelin and other congeners of the parent siderophore. The synthetic products were evaluated for their ability to bind ferric iron and promote growth of a siderophore-deficient strain of the Gram-negative bacterium Pseudomonas aeruginosa under iron restriction conditions. The results of these studies indicate coelichelin and several derivatives serve as ferric iron delivery vehicles for P. aeruginosa.
- Williams, Jade C.,Sheldon, Jessica R.,Imlay, Hunter D.,Dutter, Brendan F.,Draelos, Matthew M.,Skaar, Eric P.,Sulikowski, Gary A.
-
supporting information
p. 679 - 682
(2019/02/07)
-
- Synthesis of macrocyclic precursors of the vioprolides
-
The vioprolides are novel depsipeptides that have not been synthesized. However, they have been identified as important targets for synthesis because of their novel biological activities and challenging chemical structures. Following early work on the synthesis of a modified tetrapeptide that contained both the (E)-dehydrobutyrine and thiazoline components of vioprolide D, problems were encountered in taking an (E)-dehydrobutyrine containing intermediate further into the synthesis. A second approach to vioprolides and analogues was therefore investigated in which (E)- and (Z)-dehydrobutyrines were to be introduced by selenoxide elimination very late in the synthesis. A convergent approach to advanced macrocyclic precursors of the vioprolides was then completed using a modified hexapeptide and a dipeptidyl glycerate. In this work, it was necessary to protect the 2-hydroxyl group of the glycerate as its acetate and not as its 2,2,2-trichloroethoxycarbonate. Preliminary studies were carried out on the introduction of the required dehydrobutyrine and thiazoline components into advanced intermediates.
- Butler, Eibhlin,Florentino, Lucia,Cornut, Damien,Gomez-Campillos, Gonzalo,Liu, Hao,Regan, Andrew C.,Thomas, Eric J.
-
supporting information
p. 6935 - 6960
(2018/10/17)
-
- Heteroatom-Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity
-
Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal-ion transport. The study presented herein investigated the metal chelation of non-natural heteroatom-interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI-lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti-cancer properties demonstrated that the biological activity of HI-lissoclinamide 5 against T24 bladder cells was eleven-fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.
- Xie, Sida,Savchenko, Andrei I.,Kerscher, Marion,Grange, Rebecca L.,Krenske, Elizabeth H.,Harmer, Jeffrey R.,Bauer, Michelle J.,Broit, Natasa,Watters, Dianne J.,Boyle, Glen M.,Bernhardt, Paul V.,Parsons, Peter G.,Comba, Peter,Gahan, Lawrence R.,Williams, Craig M.
-
supporting information
p. 1465 - 1476
(2018/04/06)
-
- Total Synthesis of Plusbacin A3 and Its Dideoxy Derivative Using a Solvent-Dependent Diastereodivergent Joullié-Ugi Three-Component Reaction
-
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
-
p. 7085 - 7101
(2018/07/15)
-
- Inversion of the Side-Chain Stereochemistry of Indvidual Thr or Ile Residues in a Protein Molecule: Impact on the Folding, Stability, and Structure of the ShK Toxin
-
ShK toxin is a cysteine-rich 35-residue protein ion-channel ligand isolated from the sea anemone Stichodactyla helianthus. In this work, we studied the effect of inverting the side chain stereochemistry of individual Thr or Ile residues on the properties of the ShK protein. Molecular dynamics simulations were used to calculate the free energy cost of inverting the side-chain stereochemistry of individual Thr or Ile residues. Guided by the computational results, we used chemical protein synthesis to prepare three ShK polypeptide chain analogues, each containing either an allo-Thr or an allo-Ile residue. The three allo-Thr or allo-Ile-containing ShK polypeptides were able to fold into defined protein products, but with different folding propensities. Their relative thermal stabilities were measured and were consistent with the MD simulation data. Structures of the three ShK analogue proteins were determined by quasi-racemic X-ray crystallography and were similar to wild-type ShK. All three ShK analogues retained ion-channel blocking activity.
- Dang, Bobo,Shen, Rong,Kubota, Tomoya,Mandal, Kalyaneswar,Bezanilla, Francisco,Roux, Benoit,Kent, Stephen B. H.
-
supporting information
p. 3324 - 3328
(2017/03/17)
-
- Total Synthesis and Antibacterial Investigation of Plusbacin A3
-
The total synthesis of plusbacin A3 (1) has been accomplished using a solvent-dependent diastereodivergent Joullié-Ugi three-component reaction (JU-3CR) as a key step. Two trans-3-hydroxy-l-proline residues were constructed by combining the JU-3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization afforded plusbacin A3. Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-β-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there is a low potential for the development of resistance in S. aureus against plusbacin A3.
- Katsuyama, Akira,Paudel, Atmika,Panthee, Suresh,Hamamoto, Hiroshi,Kawakami, Toru,Hojo, Hironobu,Yakushiji, Fumika,Ichikawa, Satoshi
-
supporting information
p. 3771 - 3774
(2017/07/26)
-
- LANTHANIDE CLUSTERS AND METHODS OF USE THEREOF
-
The present invention is directed to multinuclear lanthanides chiral clusters, based on phenyl-oxazoline-amide (POxA) ligands, and to methods of use thereof. The chiral clusters of this invention are highly fluorescent with high stability.
- -
-
Paragraph 0229; 0230
(2016/01/30)
-
- Total syntheses of linear polythiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B
-
Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.
- Wilson, Zoe E.,Fenner, Sabine,Ley, Steven V.
-
supporting information
p. 1284 - 1288
(2015/01/30)
-
- Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
-
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
-
supporting information
p. 4204 - 4219
(2015/06/08)
-
- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
-
Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
- -
-
Paragraph 00104
(2014/08/19)
-
- BENZIIMIDAZOLE AND IMIDAZOPYRIDINE DERIVATIVES AS SODIUM CHANNEL MODULATORS
-
The invention relates to benzimidazole and imidazopyridine derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to new Nav1.8 modulators of formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7. X and Y are as defined in the description. Nav1.8 modulators are potentially useful in the treatment of a wide range of disorders, particularly pain.
- -
-
Page/Page column 158; 159
(2013/08/15)
-
- The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site
-
Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of β-lactam antibiotics. IPNS converts the tripeptide δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-O-methyl-d-threonine (ACmT) is not turned over by IPNS. Epimeric δ-(l-α-aminoadipoyl)-l-cysteinyl-O- methyl-d-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the β-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue.
- Clifton, Ian J.,Ge, Wei,Adlington, Robert M.,Baldwin, Jack E.,Rutledge, Peter J.
-
p. 2705 - 2709
(2013/09/02)
-
- Synthesis and structure-activity relationship (SAR) of 2-methyl-4-oxo-3- oxetanylcarbamic acid esters, a class of potent N-acylethanolamine acid amidase (NAAA) inhibitors
-
N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The β-lactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)- biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure-activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC50 = 7 nM on both rat NAAA and human NAAA).
- Ponzano, Stefano,Bertozzi, Fabio,Mengatto, Luisa,Dionisi, Mauro,Armirotti, Andrea,Romeo, Elisa,Berteotti, Anna,Fiorelli, Claudio,Tarozzo, Glauco,Reggiani, Angelo,Duranti, Andrea,Tarzia, Giorgio,Mor, Marco,Cavalli, Andrea,Piomelli, Daniele,Bandiera, Tiziano
-
p. 6917 - 6934
(2013/10/01)
-
- Tataricins A and B, two novel cyclotetrapeptides from Aster tataricus, and their absolute configuration assignment
-
Two novel cyclotetrapeptides, tataricins A and B, with a unique cyclopeptide backbone and aδ 2,4Pro side chain, were isolated from the traditional Chinese medicine Aster tataricus. Their structures and absolute configurations were determined using a combination of spectroscopic data, the advanced Marfey's method, and a total synthesis. Copyright
- Xu, Hui-Min,Yi, Hua,Zhou, Wen-Bing,He, Wen-Jun,Zeng, Gang-Zhi,Xu, Wen-Yan,Tan, Ning-Hua
-
supporting information
p. 1380 - 1383
(2013/04/23)
-
- N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships
-
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
-
experimental part
p. 4824 - 4836
(2012/07/03)
-
- Minutissamides E-L, antiproliferative cyclic lipodecapeptides from the cultured freshwater cyanobacterium cf. Anabaena sp.
-
The extract of UIC 10035, a strain obtained from a sample collected near the town of Homestead, South Florida, showed antiproliferative activity against MDA-MB-435 cells. Bioassay-guided fractionation led to the isolation of a series of cyclic lipodecapeptides, named minutissamides E-L (1-8). The planar structures were determined by analysis of HRESIMS, tandem MS, and 1D and 2D NMR data, and the stereoconfigurations were assigned by LC-MS analysis of the Marfey's derivatives after acid hydrolysis. Minutissamides E-L (1-8) exhibited antiproliferative activity against MDA-MB-435 cells with IC50 values ranging between 1 and 10 μM. The structures of minutissamides E-L (1-8) were closely related with those of the previously reported lipopeptides, puwainaphycins A-E and minutissamides A-D, characterized by the presence of a lipophilic β-amino acid and three non-standard amino acids NMeAsn, OMeThr and Dhb (α,β-dehydro-α-aminobutyric acid). The strain UIC 10035 was designated as cf. Anabaena sp. on the basis of morphological and 16S rRNA gene sequence analyses.
- Kang, Hahk-Soo,Sturdy, Megan,Krunic, Aleksej,Kim, Hyunjung,Shen, Qi,Swanson, Steven M.,Orjala, Jimmy
-
p. 6134 - 6143
(2012/11/07)
-
- Asymmetric synthesis of 2,4,6-trideoxy-4-(dimethylamino)-3-C-methyl-l- lyxohexopyranose (Lemonose)
-
l-Lemonose, the glycosidic part of (-)-lemonomycin, has been synthesized in ten steps with 18% overall yield from d-threonine. The key steps are a double, highly diastereoselective Grignard addition to a Weinreb amide and a chemoselective oxidation of a primary alcohol in the presence of a secondary alcohol, a tertiary alcohol and a tertiary amine, leading directly to the lactol. Georg Thieme Verlag Stuttgart New York.
- Bernadat, Guillaume,George, Nicolas,Couturier, Cédric,Masson, Géraldine,Schlama, Thierry,Zhu, Jieping
-
scheme or table
p. 576 - 578
(2011/04/18)
-
- Total synthesis of chloptosin: A dimeric cyclohexapeptide
-
Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme. Copyright
- Oelke, Alexander J.,Antonietti, Francesca,Bertone, Leonardo,Cranwell, Philippa B.,France, David J.,Goss, Rebecca J. M.,Hofmann, Tatjana,Knauer, Stephan,Moss, Steven J.,Skelton, Paul C.,Turner, Richard M.,Wuitschik, Georg,Ley, Steven V.
-
supporting information; experimental part
p. 4183 - 4194
(2011/06/17)
-
- Synthesis and structure - Activity relationships of N -(2-Oxo-3-oxetanyl) amides as N -acylethanolamine-hydrolyzing acid amidase inhibitors
-
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
-
experimental part
p. 5770 - 5781
(2010/10/20)
-
- 1-Acetylpyrene with dual functions as an environment-sensitive fluorophore and fluorescent photoremovable protecting group
-
A series of new fluorescent ester conjugates of carboxylic acids including amino acids was synthesized by coupling with an environment-sensitive fluorophore 1-acetylpyrene. Interestingly, the fluorescence properties of the ester conjugates and 1-acetylpyrene were found to be highly sensitive to its surrounding environment. The results obtained from the photolysis of the ester conjugates indicated that various factors like solvent, irradiation wavelength, and the structure of the conjugates govern the rate of the photocleavage.
- Jana, Avijit,Atta, Sanghamitra,Sarkar, Sujan K.,Singh, N.D. Pradeep
-
supporting information; experimental part
p. 9798 - 9807
(2011/02/22)
-
- LYSOBACTIN AMIDES
-
The invention relates to lysobactin amides and methods for their preparation, as well as their use for manufacturing medicaments for the treatment and/or prophylaxis of diseases, in particular bacterial infectious diseases.
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-
-
- Non-natural amino acids as modulating agents of the conformational space of model glycopeptides
-
The synthesis and conformational analysis in aqueous solution of different α-methyl-α-amino acid di-amides, derived from serine, threonine, β-hydroxycyclobutane-α-amino acids, and their corresponding model β-O-glucopeptides, are reported. The study reveals that the presence of an α-methyl group forces the model peptides to adopt helix-like conformations. These folded conformations are especially significant for cyclobutane derivatives. Interestingly, this feature was also observed in the corresponding model glucopeptides, thus indicating that the α-methyl group and not the β-O-glucosylation process largely determines the conformational preference of the backbone in these structures. On the other hand, atypical conformations of the glycosidic linkage were experimentally determined. Therefore, when a methyl group was located at the Cβ atom with an R configuration, the glycosidic linkage was rather rigid. Never-theless, when the S configuration was displayed, a significant degree of flexibility was observed for the glycosidic linkage, thus showing both alternate and eclipsed conformations of the ψb dihedral angle. In addition, some derivatives exhibited an unusual value for the Φ2 angle, which was far from a value of -60° expected for a conventional β-O-glycosidic linkage. In this sense, the different conformations exhibited by these molecules could be a useful tool in obtaining systems with conformational preferences "a la carte".
- Fernandez-Tejada, Alberto,Corzana, Francisco,Busto, Jesus H.,Jimenez-Oses, Gonzalo,Peregrina, Jesus M.,Avenoza, Alberto
-
supporting information; experimental part
p. 7042 - 7058
(2009/07/25)
-
- Useful reagents for introduction of Boc and Fmoc protective groups to amines: Boc-DMT and Fmoc-DMT
-
New amino-protecting reagents, Boc-DMT and Fmoc-DMT, were prepared, and found to be useful for the introduction of Boc and Fmoc groups into amines. Both the reagents can protect various amines including amino acids in good yield in aqueous media. Since the reagents are neither unstable nor irritating, they are practically useful. Georg Thieme Verlag Stuttgart.
- Hioki, Kazuhito,Kinugasa, Mizuho,Kishimoto, Michiko,Fujiwara, Miho,Tani, Shohei,Kunishima, Munetaka
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p. 1931 - 1933
(2007/10/03)
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- Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents
-
Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization.
- Niu, Chuan,Smith, Daniel,Zask, Arie,Loganzo, Frank,Discafani, Carolyn,Beyer, Carl,Greenberger, Lee,Ayral-Kaloustian, Semiramis
-
p. 4329 - 4332
(2007/10/03)
-
- Total synthesis of the ramoplanin A2 and ramoplanose aglycon
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Full details of a convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon are disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26 (residues 1,2 and 15-17), and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected L-threo-β-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 °C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist β-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. By altering the order of final couplings, two macrocyclization sites, Phe9-D-Orn10 and Gly14-Leu15, were examined. Macrocyclization at the highly successful Phe9-D-Orn10 site (89%) may benefit from both β-sheet preorganization as well as closure at a D-amine terminus within the confines of a β-turn at the end of the H-bonded antiparallel β-strands. A more modest, but acceptable macrocyclization reaction at the Gly14-Leu15 site (40-50%) found at the other end of the H-bonded antiparallel β-strands within a small flexible loop may also benefit from preorganization of the cyclization substrate, is conducted on a substrate incapable of competitive racemization, and accommodates the convergent preparation of analogues bearing depsipeptide modifications. Deliberate late-stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn1 side-chain introduction provides future access to analogues of the aglycons which themselves are equally potent or more potent than the natural products in antimicrobial assays.
- Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
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p. 1877 - 1887
(2007/10/03)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors are disclosed having the general formula:(I) wherein R1, R2, R3, R', B, Y and X are described in the description. Compositions comprising the compounds and methods for using the compounds toinhibit HCV are also disclosed.
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- Application of serine- and threonine-derived cyclic sulfamidates for the preparation of S-linked glycosyl amino acids in solution- and solid-phase peptide synthesis
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Cyclic sulfamidates were synthesized in 60% yield from L-serine and allo-L-threonine, respectively. These sulfamidates reacted with a variety of unprotected 1-thio sugars in aqueous bicarbonate buffer (pH 8) to afford the corresponding S-linked serine- and threonine-glycosyl amino acids with good diastereoselectivity (≥97%) after hydrolysis of the N-sulfates. The serine-derived sulfamidate was incorporated into a simple dipeptide to generate a reactive dipeptide substrate that underwent chemoselective ligation with a 1-thio sugar to afford an S-linked glycopeptide. This sulfamidate was also incorporated into a peptide on a solid support in conjunction with solid-phase peptide synthesis. Chemoselective ligation of a 1-thio sugar with the cyclic sulfamidate was achieved on the solid support, followed by removal of the N-sulfate. Finally, the peptide chain of the resulting support-bound S-linked glycopeptide was extended using standard peptide synthesis procedures.
- Cohen, Scott B.,Halcomb, Randall L.
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p. 2534 - 2543
(2007/10/03)
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- Total synthesis of the ramoplanin A2 and ramoplanose aglycon
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A convergent total synthesis of the ramoplanin A2 and ramoplanose aglycon is disclosed. Three key subunits composed of residues 3-9 (heptapeptide 15), pentadepsipeptide 26, and pentapeptide 34 (residues 10-14) were prepared, sequentially coupled, and cyclized to provide the 49-membered depsipeptide core of the aglycon. Key to the preparation of the pentadepsipeptide 26 incorporating the backbone ester was the asymmetric synthesis of an orthogonally protected l-threo-β-hydroxyasparagine and the development of effective and near-racemization free conditions for esterification of its hindered alcohol (EDCI, DMAP, 0 °C). The coupling sites were chosen to maximize the convergency of the synthesis including that of the three subunits, to prevent late stage racemization of carboxylate-activated phenylglycine-derived residues, and to enlist β-sheet preorganization of an acyclic macrocyclization substrate for 49-membered ring closure. As such, macrocyclization at the chosen Phe9-d-Orn10 site may benefit from both β-sheet preorganization as well as closure at a d-amine terminus. Deliberate late stage incorporation of the subunit bearing the labile depsipeptide ester and a final stage Asn1 side chain introduction provides future access to analogues of the aglycons which themselves are reported to be equally potent or more potent than the natural products in antimicrobial assays. Copyright
- Jiang, Wanlong,Wanner, Jutta,Lee, Richard J.,Bounaud, Pierre-Yves,Boger, Dale L.
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p. 5288 - 5290
(2007/10/03)
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- Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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Compounds of Formula (1.0.0): are described wherein A is for example aryl, heteroaryl or heterocyclyl, Y is preferably —C(═O)—; B is independently selected from a group of moieties, the most preferred of which are those of partial Formulas (1.1.2) and (1.1.6): and E is a single bond; oxygen; 1,1-cyclopropyl; C(CH3)2; CF2; or a bridging moiety of partial Formula (1.9.0): where R1ais hydrogen when R1has the meaning of a mono-valent substituent; and R1ais a single bond when R1has the meaning of a di-valent substituent. Said compounds are useful in methods of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.
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- SIMPLE HETEROCYCLE, 2-OXAZOLONE, AS VERSATILE BUILDING BLOCK FOR 2-AMINO ALCOHOLS. CHIRAL SYNTHESIS OF POLYHALOTHREONINES
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Smooth radical-initiated addition of CCl4 and CCl3Br to 3--2-oxazolone gives a 1:1 mixture of readily separable (4S,5R)- and (4R,5S)-4-halogeno-5-trichloromethyl-2-oxazolidinone derivatives, which serve for facile preparation of polychlorothreonines including 4,4-dichloro-2-amino-3-hydroxybutyric acid, known as antimicrobial armentomycin analog.
- Ishizuka, Tadao,Osaki, Mitsuyasu,Ishihara, Hideharu,Kunieda, Takehisa
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p. 901 - 908
(2007/10/02)
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- 2-OXO-1-AZETIDINESULFONIC ACID SALTS
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Antibacterial activity is exhibited by beta-lactams having a sulfonic acid salt substituent in the 1-position and an amino or acylamino substituent in the 3-position.
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- Monobactams. Preparation of (S)-3-Amino-2-oxoazetidine-1-sulfonic Acids from L-α-Amino-β-hydroxy Acids via Their Hydroxamic Esters
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The cyclization of the O-methylhydroxamates 13-15 afforded excellent yields of the 1-methoxyazetidinones 16-18.Reductive cleavage of the methoxy group gave N-1-unsubstituted azetidinones 9, 19, and 20 which were sulfonated and deprotected, yielding zwitterions 29-31.These materials serve as general intermediates for the preparation of a large variety of monobactam antimicrobial agents.
- Floyd, David M.,Fritz, Alan W.,Pluscec, Josip,Weaver, Eugene R.,Cimarusti, Christopher M.
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p. 5160 - 5167
(2007/10/02)
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