Structure-activity relationships of fluorinated lysophosphatidic acid analogues

Yong Xu, Junken Aoki, Kumiko Shimizu, Makiko Umezu-Goto, Kotaro Hama, Yasukazu Takanezawa, Shuangxing Yu, Gordon Mills, Hiroyuki Arai, Lian Qian, Glenn D. Prestwich

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions with seven-transmembrane G-protein-coupled receptors (GPCRs) and the nuclear hormone receptor PPARγ. To identify receptor-selective LPA analogues, we describe a series of fluorinated LPA analogues in which either the sn-1 or sn-2 hydroxyl group was replaced by a fluoro or fluoromethyl substituent. We also describe stabilized phosphonate analogues in which the bridging oxygen of the monophosphate was replaced by an α-monofluoromethylene (-CHF-) or α-difluoromethylene (-CF2-) moiety. 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. We first tested these LPA analogues on insect Sf9 cells induced to express human LPA1, LPA2, and LPA3 receptors. While none of the analogues were found to be more potent than 1-oleoyl-LPA at LPA 1 and LPA2, several LPA analogues were potent LPA 3-selective agonists. In contrast, 1-oleoyl-LPA had similar activity at all three receptors. The α-fluoromethylene phosphonate analogue 15 activated calcium release in LPA3-transfected insect Sf9 cells at a concentration 100-fold lower than that of 1-oleoyl-LPA. This activation was enantioselective, with the (2S)-enantiomer showing 1000-fold more activity than the (2R)-enantiomer. Similar results were found for calcium release in HT-29 and OVCAR8 cells. Analogue 15 was also more effective than 1-oleoyl-LPA in activating MAPK and AKT in cells expressing high levels of LPA3. The α-fluoromethylene phosphonate moiety greatly increased the half-life of 15 in cell culture. Thus, α-fluoromethylene LPA analogues are unique new phosphatase-resistant ligands that provide enantiospecific and receptor-specific biological readouts.

Original languageEnglish (US)
Pages (from-to)3319-3327
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number9
DOIs
StatePublished - May 5 2005
Externally publishedYes

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Lysophosphatidic Acid Receptors
Organophosphonates
Structure-Activity Relationship
Enantiomers
Sf9 Cells
Cytology
Calcium
Insects
Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
Cell culture
Phosphoric Monoester Hydrolases
Freezing
Hydroxyl Radical
HT29 Cells
Chemical activation
Cells
Oxygen
Ligands
Half-Life

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Xu, Y., Aoki, J., Shimizu, K., Umezu-Goto, M., Hama, K., Takanezawa, Y., ... Prestwich, G. D. (2005). Structure-activity relationships of fluorinated lysophosphatidic acid analogues. Journal of Medicinal Chemistry, 48(9), 3319-3327. https://doi.org/10.1021/jm049186t

Structure-activity relationships of fluorinated lysophosphatidic acid analogues. / Xu, Yong; Aoki, Junken; Shimizu, Kumiko; Umezu-Goto, Makiko; Hama, Kotaro; Takanezawa, Yasukazu; Yu, Shuangxing; Mills, Gordon; Arai, Hiroyuki; Qian, Lian; Prestwich, Glenn D.

In: Journal of Medicinal Chemistry, Vol. 48, No. 9, 05.05.2005, p. 3319-3327.

Research output: Contribution to journalArticle

Xu, Y, Aoki, J, Shimizu, K, Umezu-Goto, M, Hama, K, Takanezawa, Y, Yu, S, Mills, G, Arai, H, Qian, L & Prestwich, GD 2005, 'Structure-activity relationships of fluorinated lysophosphatidic acid analogues', Journal of Medicinal Chemistry, vol. 48, no. 9, pp. 3319-3327. https://doi.org/10.1021/jm049186t
Xu Y, Aoki J, Shimizu K, Umezu-Goto M, Hama K, Takanezawa Y et al. Structure-activity relationships of fluorinated lysophosphatidic acid analogues. Journal of Medicinal Chemistry. 2005 May 5;48(9):3319-3327. https://doi.org/10.1021/jm049186t
Xu, Yong ; Aoki, Junken ; Shimizu, Kumiko ; Umezu-Goto, Makiko ; Hama, Kotaro ; Takanezawa, Yasukazu ; Yu, Shuangxing ; Mills, Gordon ; Arai, Hiroyuki ; Qian, Lian ; Prestwich, Glenn D. / Structure-activity relationships of fluorinated lysophosphatidic acid analogues. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 9. pp. 3319-3327.
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AU - Takanezawa, Yasukazu

AU - Yu, Shuangxing

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