Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid

Renuka Gupte; Anjaih Siddam; Yan Lu; Wei Li; Yuko Fujiwara; Nattapon Panupinthu; Truc Chi Pham; Daniel L. Baker; Abby L. Parrill; Mari Gotoh; Kimiko Murakami-Murofushi; Susumu Kobayashi; Gordon B. Mills; Gabor Tigyi; Duane D. Miller

doi:10.1016/j.bmcl.2010.09.115

Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid

Renuka Gupte, Anjaih Siddam, Yan Lu, Wei Li, Yuko Fujiwara, Nattapon Panupinthu, Truc Chi Pham, Daniel L. Baker, Abby L. Parrill, Mari Gotoh, Kimiko Murakami-Murofushi, Susumu Kobayashi, Gordon B. Mills, Gabor Tigyi, Duane D. Miller

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA₅ GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA₅ compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.

Original language	English (US)
Pages (from-to)	7525-7528
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2010.09.115
State	Published - Dec 15 2010
Externally published	Yes

Keywords

Autotaxin
GPR92
Lysophosphatidic acid
Lysophospholipase D
NPP2

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2010.09.115

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Gupte, R., Siddam, A., Lu, Y., Li, W., Fujiwara, Y., Panupinthu, N., Pham, T. C., Baker, D. L., Parrill, A. L., Gotoh, M., Murakami-Murofushi, K., Kobayashi, S., Mills, G. B., Tigyi, G., & Miller, D. D. (2010). Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid. Bioorganic and Medicinal Chemistry Letters, 20(24), 7525-7528. https://doi.org/10.1016/j.bmcl.2010.09.115

Gupte, R, Siddam, A, Lu, Y, Li, W, Fujiwara, Y, Panupinthu, N, Pham, TC, Baker, DL, Parrill, AL, Gotoh, M, Murakami-Murofushi, K, Kobayashi, S, Mills, GB, Tigyi, G & Miller, DD 2010, 'Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 24, pp. 7525-7528. https://doi.org/10.1016/j.bmcl.2010.09.115

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abstract = "Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA5 GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA5 compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.",

keywords = "Autotaxin, GPR92, Lysophosphatidic acid, Lysophospholipase D, NPP2",

author = "Renuka Gupte and Anjaih Siddam and Yan Lu and Wei Li and Yuko Fujiwara and Nattapon Panupinthu and Pham, {Truc Chi} and Baker, {Daniel L.} and Parrill, {Abby L.} and Mari Gotoh and Kimiko Murakami-Murofushi and Susumu Kobayashi and Mills, {Gordon B.} and Gabor Tigyi and Miller, {Duane D.}",

note = "Funding Information: This research was supported by NIH Grant CA92160 (G.T.), Van Vleet Professorship (D.M.), Breast Cancer Research Foundation (N.P.) and Lpath Inc. (G.M.).",

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AU - Gupte, Renuka

AU - Siddam, Anjaih

AU - Lu, Yan

AU - Li, Wei

AU - Fujiwara, Yuko

AU - Panupinthu, Nattapon

AU - Pham, Truc Chi

AU - Baker, Daniel L.

AU - Parrill, Abby L.

AU - Gotoh, Mari

AU - Murakami-Murofushi, Kimiko

AU - Kobayashi, Susumu

AU - Mills, Gordon B.

AU - Tigyi, Gabor

AU - Miller, Duane D.

N1 - Funding Information: This research was supported by NIH Grant CA92160 (G.T.), Van Vleet Professorship (D.M.), Breast Cancer Research Foundation (N.P.) and Lpath Inc. (G.M.).

PY - 2010/12/15

Y1 - 2010/12/15

N2 - Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA5 GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA5 compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.

AB - Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA5 GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA5 compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.

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KW - GPR92

KW - Lysophosphatidic acid

KW - Lysophospholipase D

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Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid

Abstract

Keywords

ASJC Scopus subject areas

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