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

doi:10.1016/j.bmcl.2004.08.019

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 journal › Article › peer-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 language	English
Pages (from-to)	5323-5328
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	14
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2004.08.019
Publication status	Published - 2004 Nov 1
Externally published	Yes

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

UN SDGs

This output contributes to the following Sustainable Development Goal(s)

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title = "Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors",

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.",

keywords = "Alkyl LPA, Cell migration, Epoxide ring opening, Fluorinated alkyl LPA analogues",

author = "Yong Xu and Masayuki Tanaka and Hiroyuki Arai and Junken Aoki and Prestwich, {Glenn D.}",

note = "Funding Information: We thank the Human Frontier Science Program (RG0073-2000B) and the NIH (HL070231) for support at the University of Utah and the College of Pharmacy at University of Tokyo. ",

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doi = "10.1016/j.bmcl.2004.08.019",

language = "English",

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T1 - Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors

AU - Xu, Yong

AU - Tanaka, Masayuki

AU - Arai, Hiroyuki

AU - Aoki, Junken

AU - Prestwich, Glenn D.

N1 - Funding Information: We thank the Human Frontier Science Program (RG0073-2000B) and the NIH (HL070231) for support at the University of Utah and the College of Pharmacy at University of Tokyo.

PY - 2004/11/1

Y1 - 2004/11/1

N2 - 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.

AB - 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.

KW - Alkyl LPA

KW - Cell migration

KW - Epoxide ring opening

KW - Fluorinated alkyl LPA analogues

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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