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  1. Article ; Online: Progress toward the Total Synthesis of Lymphostins: Preparation of a Functionalized Tetrahydropyrrolo[4,3,2-

    Seiler, Grant S / Hughes, Chambers C

    The Journal of organic chemistry

    2019  Volume 84, Issue 14, Page(s) 9339–9343

    Abstract: The lymphostins are a family of closely related pyrrolo[4,3,2- ...

    Abstract The lymphostins are a family of closely related pyrrolo[4,3,2-
    MeSH term(s) Molecular Structure ; Oxidation-Reduction ; Quinolines/chemical synthesis
    Chemical Substances Quinolines
    Language English
    Publishing date 2019-06-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.9b01041
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4473: Show issues Location:
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  2. Article: Progress toward the Total Synthesis of Lymphostins: Preparation of a Functionalized Tetrahydropyrrolo[4,3,2-de]quinoline and Unusual Oxidative Dimerization

    Seiler, Grant S / Hughes, Chambers C

    Journal of organic chemistry. 2019 June 19, v. 84, no. 14

    2019  

    Abstract: The lymphostins are a family of closely related pyrrolo[4,3,2-de]quinoline natural products produced by Streptomyces and Salinispora actinobacteria. Neolymphostin A was recently shown to strongly inhibit phosphoinositide 3-kinase (PI3K) and the mammalian ...

    Abstract The lymphostins are a family of closely related pyrrolo[4,3,2-de]quinoline natural products produced by Streptomyces and Salinispora actinobacteria. Neolymphostin A was recently shown to strongly inhibit phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in a covalent manner via conjugation to a catalytic lysine residue in the ATP-binding pocket of the enzymes, making this metabolite the first reported covalent kinase inhibitor from a bacterium. A flexible and efficient synthetic route toward these alkaloids would allow for improvements in their solubility, stability, and selectivity and help to deliver a viable drug candidate. We have since established a short synthesis to methyl 8-bromo-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline-4-carboxylate via a conjugate addition/intramolecular Ullman reaction sequence. However, attempts to oxidize this intermediate to the pyrrolo[4,3,2-de]quinoline characteristic of the lymphostins resulted in formation of either a 2-oxo-1,2-dihydropyrrolo[4,3,2-de]quinoline or an unusual N,C-linked tetrahydropyrroloquinoline-pyrroloquinoline heterodimer. We expect that key modifications to the tetrahydropyrroloquinoline intermediate prior to oxidation should prevent these side reactions and pave the way for the completion of the synthesis.
    Keywords alkaloids ; bacteria ; binding sites ; catalytic activity ; dimerization ; drugs ; enzyme inhibitors ; lysine ; mammals ; metabolites ; organic chemistry ; oxidation ; phosphatidylinositol 3-kinase ; quinoline ; rapamycin ; solubility ; Streptomyces
    Language English
    Dates of publication 2019-0619
    Size p. 9339-9343.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.9b01041
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

    Castro-Falcón, Gabriel / Seiler, Grant S / Demir, Özlem / Rathinaswamy, Manoj K / Hamelin, David / Hoffmann, Reece M / Makowski, Stefanie L / Letzel, Anne-Catrin / Field, Seth J / Burke, John E / Amaro, Rommie E / Hughes, Chambers C

    Journal of medicinal chemistry

    2018  Volume 61, Issue 23, Page(s) 10463–10472

    Abstract: Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ...

    Abstract Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC
    MeSH term(s) Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Esters/chemistry ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases/chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Conformation ; Quinolines/chemistry ; Quinolines/metabolism ; Quinolines/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors
    Chemical Substances Enzyme Inhibitors ; Esters ; Phosphoinositide-3 Kinase Inhibitors ; Quinolines ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2018-11-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b00975
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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