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 journalArticlepeer-review

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
Externally publishedYes

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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