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 journalArticle

    19 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 languageEnglish (US)
    Pages (from-to)7525-7528
    Number of pages4
    JournalBioorganic and Medicinal Chemistry Letters
    Volume20
    Issue number24
    DOIs
    StatePublished - Dec 15 2010

    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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  • Cite this

    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