Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors

Yong Xu, Masayuki Tanaka, Hiroyuki Arai, Junken Aoki, Glenn D. Prestwich

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

We describe an efficient method for the synthesis of alkyl lysophosphatidic acid (LPA) analogs as well as alkyl LPA mono- and difluoromethylene phosphonate analogs. Each alkyl LPA analog was evaluated for subtype-specific LPA receptor agonist activity using a cell migration assay for LPA 1 activation in cancer cells and an intracellular calcium mobilization assay for LPA 2 and LPA 3 activation. Alkyl LPAs induced pronounced cell migration activity with equivalent or higher potency than sn-1-oleoyl LPA, while the alkyl LPA fluoromethylene phosphonates proved to be less potent agonists in this assay. However, each alkyl LPA analog activated Ca 2+ release by activation of LPA 2 and LPA 3 receptors. Interestingly, the absolute configuration of the sn-2 hydroxyl group of the alkyl LPA analogs was not recognized by any of the three LPA receptors. The use of alkyl LPA analogs further expands the scope of structure-activity studies, which will better define LPA-LPA receptor interactions.

Original languageEnglish
Pages (from-to)5323-5328
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number21
DOIs
Publication statusPublished - 2004 Nov 1
Externally publishedYes

Keywords

  • Alkyl LPA
  • Cell migration
  • Epoxide ring opening
  • Fluorinated alkyl LPA analogues

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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