Abstract
An efficient stereocontrolled synthesis afforded alkoxymethylene- phosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual LPA1-LPA3 receptors and CHO cells expressing LPA4. In addition, activation of a PPARγ reporter gene construct expressed in CV-1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G-protein-coupled receptor family and the intracellular LPA receptor PPARγ. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29colon cancer cells, which exclusively express LPA2, and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA1, LPA2, and LPA3. Unexpectedly, reverse phase protein arrays showed that four MP-LPA and MP-PA analogues selectively activated downstream signaling in HT-29 cells with greater potency than LPA. In particular, the oleoyl MP-LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT-29cells in a concentration-dependent manner. In contrast, the four MP-LPA and MP-PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA2 receptor subtype, while simultaneously suppressing signaling through the LPA1 and LPA3 subtypes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1789-1798 |
| Number of pages | 10 |
| Journal | ChemMedChem |
| Volume | 2 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 10 2007 |
| Externally published | Yes |
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Keywords
- Agonists
- GPCRs
- Lysophosphatidic acid
- Methylenephosphonates
- Receptors
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry
- Molecular Medicine
Cite this
Alkoxymethylenephosphonate analogues of (Lyso)phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor. / Gajewiak, Joanna; Tsukahara, Ryoko; Tsukahara, Tamotsu; Yu, Shuanxing; Lu, Yiling; Murph, Mandi; Mills, Gordon; Tigyi, Gabor; Prestwich, Glenn D.
In: ChemMedChem, Vol. 2, No. 12, 10.12.2007, p. 1789-1798.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alkoxymethylenephosphonate analogues of (Lyso)phosphatidic acid stimulate signaling networks coupled to the LPA2 receptor
AU - Gajewiak, Joanna
AU - Tsukahara, Ryoko
AU - Tsukahara, Tamotsu
AU - Yu, Shuanxing
AU - Lu, Yiling
AU - Murph, Mandi
AU - Mills, Gordon
AU - Tigyi, Gabor
AU - Prestwich, Glenn D.
PY - 2007/12/10
Y1 - 2007/12/10
N2 - An efficient stereocontrolled synthesis afforded alkoxymethylene- phosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual LPA1-LPA3 receptors and CHO cells expressing LPA4. In addition, activation of a PPARγ reporter gene construct expressed in CV-1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G-protein-coupled receptor family and the intracellular LPA receptor PPARγ. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29colon cancer cells, which exclusively express LPA2, and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA1, LPA2, and LPA3. Unexpectedly, reverse phase protein arrays showed that four MP-LPA and MP-PA analogues selectively activated downstream signaling in HT-29 cells with greater potency than LPA. In particular, the oleoyl MP-LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT-29cells in a concentration-dependent manner. In contrast, the four MP-LPA and MP-PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA2 receptor subtype, while simultaneously suppressing signaling through the LPA1 and LPA3 subtypes.
AB - An efficient stereocontrolled synthesis afforded alkoxymethylene- phosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual LPA1-LPA3 receptors and CHO cells expressing LPA4. In addition, activation of a PPARγ reporter gene construct expressed in CV-1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G-protein-coupled receptor family and the intracellular LPA receptor PPARγ. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT-29colon cancer cells, which exclusively express LPA2, and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA1, LPA2, and LPA3. Unexpectedly, reverse phase protein arrays showed that four MP-LPA and MP-PA analogues selectively activated downstream signaling in HT-29 cells with greater potency than LPA. In particular, the oleoyl MP-LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT-29cells in a concentration-dependent manner. In contrast, the four MP-LPA and MP-PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA2 receptor subtype, while simultaneously suppressing signaling through the LPA1 and LPA3 subtypes.
KW - Agonists
KW - GPCRs
KW - Lysophosphatidic acid
KW - Methylenephosphonates
KW - Receptors
UR - http://www.scopus.com/inward/record.url?scp=48849087088&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48849087088&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200700111
DO - 10.1002/cmdc.200700111
M3 - Article
C2 - 17952880
AN - SCOPUS:48849087088
VL - 2
SP - 1789
EP - 1798
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 12
ER -