1066-52-0Relevant academic research and scientific papers
Ion-molecule reactions of O,S-dimethyl methylphosphonothioate: Evidence for intramolecular sulfur oxidation during VX perhydrolysis
McAnoy, Andrew M.,Williams, Jilliarne,Paine, Martin R. L.,Rogers, Michael L.,Blanksby, Stephen J.
, p. 9319 - 9327 (2009)
(Chemical Equation Presented) The alkaline perhydrolysis of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) was investigated by studying the ion-molecule reactions of HOO- with O,S-dimethyl methylphosphonothioate in a modified linear ion-trap mass spectrometer. In addition to simple proton transfer, two other abundant product ions are observed at m/z 125 and 109 corresponding to the S-methyl methylphosphonothioate and methyl methylphosphonate anions, respectively. The structure of these product ions is demonstrated by a combination of collision-induced dissociation and isotope-labeling experiments that also provide evidence for their formation by nucleophilic reaction pathways, namely, (i) SN2 at carbon to yield the S-methyl methylphosphonothioate anion and (ii) nucleophilic addition at phosphorus affording a reactive pentavalent intermediate that readily undergoes internal sulfur oxidation and concomitant elimination of CH3SOH to yield the methyl methylphosphonate anion. Consistent with previous solution phase observations of VX perhydrolysis, the toxic P-O cleavage product is not observed in this VX model system and theoretical calculations identify P-O cleavage to be energetically uncompetitive. Conversely, intramolecular sulfur oxidation is calculated to be extremely exothermic and kinetically accessible explaining its competitiveness with the facile gas phase proton transfer process. Elimination of a sulfur moiety deactivates the nerve agent VX and thus the intramolecular sulfur oxidation process reported here is also able to explain the selective perhydrolysis of the nerve agent to relatively nontoxic products.
Synthesis and in vivo antitumor evaluation of an orally active potent phosphonamidate derivative targeting IDO1/IDO2/TDO
Feng, Xi,Shen, Pei,Wang,Li,Bian, Jinlei
, p. 214 - 223 (2019)
Targeting Trp-Kyn pathways has been identified as an attractive approach for the cancer immunotherapies. In this study, a novel phosphonamidate containing compound was designed, synthesized and evaluated for its inhibitory activity against key dioxygenase
Asymmetric synthesis of a cyclopropanecarboxylic acid derivative–the potential agonist/antagonist of GABA receptors
Krysiak, Jerzy,Mikina, Maciej,Rzewnicka, Aneta,Sobczak, Agata,?urawiński, Remigiusz,Sieroń, Les?aw
, (2022/01/20)
The synthesis of enantiomerically pure (1S,2S,S P)-1-[hydroxy(methyl)phosphonyl]-2-aminocyclopropanecarboxylic acid (1) (a potential agonist/antagonist of GABA receptors) was accomplished in six steps based on optically inactive methyl 2-[metho
HEADGROUP LIPID COMPOUNDS AND COMPOSITIONS FOR INTRACELLULAR DELIVERY OF THERAPEUTIC AGENTS
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Paragraph 00402, (2021/04/01)
The application relates to lipids of Formula (A-1) and compositions involving the same. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) include such a lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) further including therapeutic and/ or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.
Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer
Du, Qianming,Feng, Xi,Wang, Yinuo,Xu, Xi,Zhang, Yan,Qu, Xinliang,Li, Zhiyu,Bian, Jinlei
, (2019/08/26)
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.
New method for synthesizing substituted phosphinate
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Paragraph 0052; 0055-0056, (2017/12/27)
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.
Chemical synthesis and molecular recognition of phosphatase-resistant analogues of phosphatidylinositol-3-phosphate
Xu, Yong,Lee, Stephanie A.,Kutateladze, Tatiana G.,Sbrissa, Diego,Shisheva, Assia,Prestwich, Glenn D.
, p. 885 - 897 (2007/10/03)
The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. To provide chemical tools to study the changes in cell physiology mediated by these lipids, three new metabolically stabilized (ms) analogues of phosphatidylinositol-3-phosphate (Ptdlns(3)P) were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-(monofluoromethyl)phosphonate and 3-phosphorothioate analogues of Ptdlns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of Ptdlns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl, and dibutyryl chains. In addition, we introduce a new phosphorylation reagent, (monofluoromethyl)phosphonyl chloride, which has general applications for the preparation of "pKa-matched" monofluorophosphonates. These ms-Ptdlns(3)P analogues exhibited reduced binding activities with 15N-labeled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-Ptdlns(3)P analogues into membrane-mimetic dodecylphosphocholine micelles. In addition, the Ptdlns(3)P analogues with dioleoyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis.
A convenient two-step one-pot synthesis of phosphonamidates
Mlodnosky, Karyn L.,Holmes, H. Michael,Lam, Vinh Q.,Berkman, Clifford E.
, p. 8803 - 8806 (2007/10/03)
Phosphonamidates are formed in high yield from a one-pot sequential reaction of a phosphonyl dichloride with an alcohol and then an amine in the presence of catalytic 1H-tetrazole. Undesired disubstitution of the phoshphonyl dichloride by the alcohol or the amine is minimal due to the presence of tetrazole.
Convenient "one-pot" synthesis of chlorophosphonates, chlorophosphates and chlorophosphoramides from the corresponding benzyl esters
Saady, Mourad
, p. 4785 - 4786 (2007/10/02)
Selective monodeprotection of alkyl phosphonate, phosphate and phosphoramide benzyl esters using quinuclidine and chlorination of the subsequent salts allows preparation of various alkyl phosphonochloridates, monochlorophosphates and monochlorophosphoramides in a convenient "one-pot" procedure.
