- Analogues with fluorescent leaving groups for screening and selection of enzymes that efficiently hydrolyze organophosphorus nerve agents
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Enzymes that efficiently hydrolyze highly toxic organophosphorus nerve agents could potentially be used as medical countermeasures. As sufficiently active enzymes are currently unknown, we synthesized twelve fluorogenic analogues of organophosphorus nerve agents with the 3-chloro-7-oxy-4- methylcoumarin leaving group as probes for high-throughput enzyme screening. This set included analogues of the pesticides paraoxon, parathion, and dimefox, and the nerve agents DFP, tabun, sarin, cyclosarin, soman, VX, and Russian-VX. Data from inhibition of acetylcholinesterase, in vivo toxicity tests of a representative analogue (cyclosarin), and kinetic studies with phosphotriesterase (PTE) from Pseudomonas diminuta, and a mammalian serum paraoxonase (PON1), confirmed that the analogues mimic the parent nerve agents effectively. They are suitable tools for high-throughput screens for the directed evolution of efficient nerve agent organophosphatases.
- Brise?o-Roa, Luis,Hill, Jim,Notman, Stuart,Sellers, David,Smith, Andy P.,Timperley, Christopher M.,Wetherell, Janet,Williams, Nichola H.,Williams, Gareth R.,Fersht, Alan R.,Griffiths, Andrew D.
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Read Online
- Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer
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Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10–21 nM, hIDO1 IC50 = 78–121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
- Du, Qianming,Feng, Xi,Wang, Yinuo,Xu, Xi,Zhang, Yan,Qu, Xinliang,Li, Zhiyu,Bian, Jinlei
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- Synthesis of the Tripeptides Tyr-Thr-Lys Phosphorylated with Isopropyl Methyl- and (Deuteromethyl)phosphonochloridates as Reference Standards for the Analysis of Biomedical Samples
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A procedure for the phosphorylation of the tripeptide Tyr-Thr-Lys with isopropyl methyl- or (deuteromethyl)phosphonochloridate is developed. The phosphorylated tripeptides are intended for use as reference standards in the analysis of blood samples of people suspected to have been exposed to acetylcholinesterase inhibitors. Conditions of hromatographic separation and purification of the synthesized compounds are determined and optimized, which ensures the preparation of high-purity phosphorylated tripeptides.
- Rodin,Baygildiev,Krylov,Osipov,Krylov,Yashkir,Rybalchenko
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p. 2103 - 2107
(2019/11/29)
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- New method for synthesizing substituted phosphinate
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The invention discloses a new method for synthesizing substituted phosphinate. The method comprises the step of generating the substituted phosphinate by reducing halogenated phosphonate under the effect of a reducing agent. The optimal preparation method for the substituted phosphinate is screened through a large number of experiments according to the invention; the whole process is reasonably designed; the technological operation is simple and efficient; especially, the optimal reaction conditions are screened, including reaction solvent, reaction temperature, reaction time and optimal reaction pH value; the reaction yield is obviously increased; the yield reaches up to 85-95%; the side reaction is less; the production cost is greatly lowered; the industrial production can be realized; and the method has a wide application prospect.
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Paragraph 0022; 0025-0026
(2017/12/27)
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- Solid-phase synthesis of phosphonylated peptides
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We report the solid-phase syntheses of two series of phosphonylated peptides using Fmoc-protected amino acids. The peptides corresponded to regions containing phosphonylated Ser195 in the active site of butyrylcholinesterase and Tyr411 of human serum albu
- MacDonald, Mary,Lanier, Marion,Cashman, John
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supporting information; experimental part
p. 1951 - 1954
(2010/10/19)
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- Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents
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The organophosphorus nerve agents sarin, soman, cyclosarin and tabun phosphylate a tyrosine residue on albumin in human blood. These adducts may offer relatively long-lived biological markers of nerve agent exposure that do not 'age' rapidly, and which ar
- Williams, Nichola H.,Harrison, John M.,Read, Robert W.,Black, Robin M.
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p. 627 - 639
(2008/03/13)
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- New modified nucleoside 5′-triphosphates: Synthesis, properties towards DNA polymerases, stability in blood serum and antiviral activity
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A series of new nucleoside 5'-triphosphate mimetics, 2,3,5,6, 8-10, modified at the glycone and all three phosphate residues, have been synthesised and studied. These compounds only bear the enzymatically labile anhydride bond between the α and β phosphor
- Shipitsin, Alexander V.,Victorova, Lyubov S.,Shirokova, Elena A.,Dyatkina, Natalya B.,Goryunova, Lyudmila E.,Beabealashvilli, Robert Sh,Hamilton, Cliris J.,Roberts, Stanley M.,Krayevsky, Alexander
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p. 1039 - 1050
(2007/10/03)
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