- Total and Semisyntheses of Polymyxin Analogues with 2-Thr or 10-Thr Modifications to Decipher the Structure-Activity Relationship and Improve the Antibacterial Activity
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Herein, we report the total and semisyntheses of a series of polymyxin analogues with 2-Thr and 10-Thr modifications to reveal the structure-activity relationship (SAR), which has not been fully elucidated previously. We employed two total-synthetic strategies to facilitate the diversified replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic approaches were utilized to achieve selective esterification of 2-Thr or dual esterification of both 2- and 10-Thr. Based on the results of in vitro antibacterial assays, SAR analysis implicated that the replacement of 2-/10-Thr with amino acids carrying hydrophobic side chains can maintain the activity against Pseudomonas aeruginosa but had varied effects on other tested Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr achieved excellent antibacterial activity, and the compound 76 exhibited 2-8-fold higher activity against different strains and lower toxicity toward the HK-2 cell line. This work explored the SAR of polymyxin 2-/10-Thr and provided a promising strategy for the development of novel polymyxin derivatives.
- Li, Jian,Guan, Dongliang,Chen, Feifei,Shi, Weiwei,Lan, Lefu,Huang, Wei
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p. 5746 - 5765
(2021/06/01)
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- Preparation method of N alpha-fluorenylmethoxycarbonyl-N gamma-(4, 4-dimethyl-2,6-dioxocyclohexylidene) ethyl-butyric acid
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The invention provides a preparation method of (2S)-4-[[1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] amino]-2-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] butyric acid, and mainly solves the technical problems that an existing preparation method is com
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Paragraph 0017-0020
(2019/10/17)
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- Activation of lysine-specific demethylase 1 inhibitor peptide by redox-controlled cleavage of a traceless linker
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We have previously employed cyclization of a linear peptide as a strategy to modulate peptide function and properties, but cleavage to regenerate the linear peptide left parts of the linker structure on the peptide, interfering with its activity. Here, we focused on cyclization of a linear peptide via a “traceless” disulfide-based linkage that would be cleaved and completely removed in a reducing environment, regenerating the original linear peptide without any linker-related structure. Thus, the linker would serve as a redox switch that would be activated in the intracellular environment. We applied this strategy to a lysine-specific demethylase 1 (LSD1) inhibitor peptide 1. The resulting cyclic peptide 2 exhibited approximately 20 times weaker LSD1-inhibitory activity than peptide 1. Upon addition of reducing reagent, the linker was completely removed to regenerate the linear peptide 1, with full restoration of the LSD1-inhibitory activity. In addition, the cyclic peptide was far less susceptible to proteolysis than the linear counterpart. Thus, this switch design not only enables control of functional activity, but also improves stability. This approach should be applicable to a wide range of peptides, and may be useful in the development of peptide pharmaceuticals.
- Amano, Yuichi,Umezawa, Naoki,Sato, Shin,Watanabe, Hisami,Umehara, Takashi,Higuchi, Tsunehiko
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p. 1227 - 1234
(2017/02/05)
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- OPTICAL IMAGING PROBES
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The present invention relates to methods of visualising cells especially although not exclusively in vivo using a dye, such as a dendrimer-dye molecule or polybranched-dye molecule which is internalised by the cells and thus permits subsequent visualisation by confocal fluorescence endomicroscopy or other optical detectors. There is also provided internally quenched probes for use in visualising cells especially although not exclusively in vivo by confocal fluorescence endomicroscopy and the use of internally quenched probes in combination with confocal fluorescence endomicroscopy, for visualising cells by virtue of internalisation and dequenching of a probe by the cells. In a particular embodiment the cells are activated neutrophils, such as within the lung of a subject.
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Paragraph 0155; 0156
(2014/05/20)
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- Solid-phase synthesis of C-terminal peptide libraries for studying the specificity of enzymatic protein prenylation
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Prenylation is an essential post-translational modification in all eukaryotes. Here we describe the synthesis of a 340-member library of peptides containing free C-termini on cellulose membranes. The resulting library was then used to probe the specificit
- Wang, Yen-Chih,Distefano, Mark D.
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supporting information; experimental part
p. 8228 - 8230
(2012/09/22)
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- Introduction of functional groups into peptides via N-alkylation
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An optimized protocol for the mild and selective Fukuyama-Mitsunobu reaction was used for mono- and di-N-alkylation on solid support. Thereby, nonfunctionalized aliphatic and aromatic residues are quickly introduced into transiently protected, primary ami
- Demmer,Dijkgraaf,Schottelius,Wester,Kessler
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supporting information; experimental part
p. 2015 - 2018
(2009/04/18)
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- An appraisal of new variants of Dde amine protecting group for solid phase peptide synthesis
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A series of new variants of Dde, substituted at the exocyclic alkene position have been developed and their application in solid phase peptide synthesis assessed. The new derivatives offer complete resistance towards 20% piperidine in DMF and provide a considerable barrier towards N→N'-intramolecular migration.
- Chhabra, Siri Ram,Hothi, Bhupinder,Evans, David J.,White, Peter D.,Bycroft, Barrie W.,Chan, Weng C.
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p. 1603 - 1606
(2007/10/03)
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