- Selective activation of organocatalysts by specific signals
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Reminiscent of signal transduction in biological systems, artificial catalysts whose activity can be controlled by physical or chemical signals would be of high interest in the design of chemical systems that can respond to their environment. Self-immolative chemistry offers a generic method for the development of catalysts that can be activated by different signals. To demonstrate the versatility of that concept, we synthesized organocatalysts that can be activated by three different signals and that can be used to control two different reactions. In this way the organocatalyst proline is designed as a pro-catalyst that is activated either by the chemical signal H2O2, by light or by the enzyme penicillin acylase. The pro-catalysts were used to exert temporal control over the rate of an aldol reaction and a Michael reaction.
- Maity, Chandan,Trausel, Fanny,Eelkema, Rienk
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p. 5999 - 6005
(2018/07/25)
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- Diacyl Disulfide: A Reagent for Chemoselective Acylation of Phenols Enabled by 4-(N,N-Dimethylamino)pyridine Catalysis
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A general and excellent acylation reagent, diacyl disulfide, was uncovered for efficient ester formation enabled by DMAP (4-(N,N-dimethylamino)pyridine) catalysis. This protocol offered a promising synthetic platform on site-selective acylation of phenolic and primary aliphatic hydroxyl groups, which greatly expanded the realm of protecting group chemistry. The importance of the reagent was also reflected by its excellent moisture tolerance, high efficiency, and potential in synthetic chemistry and biologically meaningful natural product modification.
- Liu, Hong-Xin,Dang, Ya-Qian,Yuan, Yun-Fei,Xu, Zhi-Fang,Qiu, Sheng-Xiang,Tan, Hai-Bo
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supporting information
p. 5584 - 5587
(2016/11/17)
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- Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization
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Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K+ channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase-a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders.
- Zakhari, Joseph S.,Kinoyama, Isao,Hixon, Mark S.,Di Mola, Antonia,Globisch, Daniel,Janda, Kim D.
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supporting information; experimental part
p. 6203 - 6209
(2011/12/02)
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- Are PhAcOZ and Nsc suitable Nα-protecting groups for protease-catalysed peptide synthesis?
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Protecting groups are necessary chemical tools in peptide synthesis. In protease-catalysed peptide synthesis they exert influence both on enzyme-substrate binding and on solubility. In this study, we have investigated the usability of various PhAcOZ- and Nsc-protected amino acids for protease-catalysed peptide synthesis. PhAcOZ-protected peptides were obtained in high yields using papain and thermolysin. In contrast to this, Nsc, as a base-labile ct-amino protecting group, is not suitable for biocatalytic synthesis under the conditions employed.
- Braun,Kuhl
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p. 310 - 312
(2007/10/03)
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- Chemoenzymatic synthesis of a characteristic phosphorylated and glycosylated peptide fragment of the large subunit of mammalian RNA polymerase II
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The covalent modification of proteins by phosphorylation and addition of GlcNAc residues are important regulatory processes which mediate biological signal transduction. For instance, the cytosolic form of RNA polymerase II is heavily glycosylated but dur
- Pohl, Torsten,Waldmann, Herbert
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p. 6702 - 6710
(2007/10/03)
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