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

23 Scopus citations

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
State	Published - 1 Nov 2004
Externally published	Yes

Keywords

Alkyl LPA
Cell migration
Epoxide ring opening
Fluorinated alkyl LPA analogues

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10.1016/j.bmcl.2004.08.019

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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.\}",

year = "2004",

month = nov,

day = "1",

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

language = "英語",

volume = "14",

pages = "5323--5328",

journal = "Bioorganic and Medicinal Chemistry Letters",

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publisher = "Elsevier Ltd",

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TY - JOUR

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.

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

UR - https://www.scopus.com/pages/publications/5344244761

U2 - 10.1016/j.bmcl.2004.08.019

DO - 10.1016/j.bmcl.2004.08.019

M3 - 記事

C2 - 15454220

AN - SCOPUS:5344244761

SN - 0960-894X

VL - 14

SP - 5323

EP - 5328

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 21

ER -

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

Abstract

Keywords

UN SDGs

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