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Synthesis of Monofluorinated Analogues of Lysophosphatidic Acid.

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Title: Synthesis of Monofluorinated Analogues of Lysophosphatidic Acid.
Authors: Yong Xu, Lian Qian, Prestwich, Glenn D.
Source: Journal of Organic Chemistry. 6/27/2003, Vol. 68 Issue 13, p5320. 11p. 6 Diagrams, 1 Chart, 1 Graph.
Subjects: Lysophospholipids, Organofluorine compounds
Abstract: Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with the nuclear hormone receptor PPARγ. Synthesis and biological activities of fluorinated analogues of LPA are still relatively unknown. In an effort to identify receptor-selective LPA analogues and to document in detail the structure-activity relationships of fluorinated LPA isosteres, we describe a series of monofluorinated LPA analogues in which either the sn-1 or the sn-2 hydroxy group was replaced by fluorine, or the bridging oxygen in the monophosphate was replaced by an α-monofluoromethylene (-CHF-) moiety. The sn-1 or sn-2 monofluorinated LPA analogues were enantiospecifically prepared from chiral protected glycerol synthons, and the α-monofluoromethylene-substituted LPA analogues were prepared from a racemic epoxide with use of a hydrolytic kinetic resolution. The sn-2 and sn-1 fluoro LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. The α-monofluoromethylene LPA analogues were unique new nonhydrolyzable ligands with surprising enantiospecific and receptor-specific biological readouts, with one compound showing a 1000-fold higher activity than native LPA for one receptor subtype. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Organic Chemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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Header DbId: egs
DbLabel: Engineering Source
An: 10207208
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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  Data: Synthesis of Monofluorinated Analogues of Lysophosphatidic Acid.
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  Data: <searchLink fieldCode="AR" term="%22Yong+Xu%22">Yong Xu</searchLink><br /><searchLink fieldCode="AR" term="%22Lian+Qian%22">Lian Qian</searchLink><br /><searchLink fieldCode="AR" term="%22Prestwich%2C+Glenn+D%2E%22">Prestwich, Glenn D.</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Organic+Chemistry%22">Journal of Organic Chemistry</searchLink>. 6/27/2003, Vol. 68 Issue 13, p5320. 11p. 6 Diagrams, 1 Chart, 1 Graph.
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  Data: <searchLink fieldCode="DE" term="%22Lysophospholipids%22">Lysophospholipids</searchLink><br /><searchLink fieldCode="DE" term="%22Organofluorine+compounds%22">Organofluorine compounds</searchLink>
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  Label: Abstract
  Group: Ab
  Data: Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with the nuclear hormone receptor PPARγ. Synthesis and biological activities of fluorinated analogues of LPA are still relatively unknown. In an effort to identify receptor-selective LPA analogues and to document in detail the structure-activity relationships of fluorinated LPA isosteres, we describe a series of monofluorinated LPA analogues in which either the sn-1 or the sn-2 hydroxy group was replaced by fluorine, or the bridging oxygen in the monophosphate was replaced by an α-monofluoromethylene (-CHF-) moiety. The sn-1 or sn-2 monofluorinated LPA analogues were enantiospecifically prepared from chiral protected glycerol synthons, and the α-monofluoromethylene-substituted LPA analogues were prepared from a racemic epoxide with use of a hydrolytic kinetic resolution. The sn-2 and sn-1 fluoro LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. The α-monofluoromethylene LPA analogues were unique new nonhydrolyzable ligands with surprising enantiospecific and receptor-specific biological readouts, with one compound showing a 1000-fold higher activity than native LPA for one receptor subtype. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Organic Chemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1021/jo020729l
    Languages:
      – Code: eng
        Text: English
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      Pagination:
        PageCount: 11
        StartPage: 5320
    Subjects:
      – SubjectFull: Lysophospholipids
        Type: general
      – SubjectFull: Organofluorine compounds
        Type: general
    Titles:
      – TitleFull: Synthesis of Monofluorinated Analogues of Lysophosphatidic Acid.
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            NameFull: Yong Xu
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            NameFull: Lian Qian
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            NameFull: Prestwich, Glenn D.
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            – D: 27
              M: 06
              Text: 6/27/2003
              Type: published
              Y: 2003
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              Value: 00223263
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              Value: 68
            – Type: issue
              Value: 13
          Titles:
            – TitleFull: Journal of Organic Chemistry
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