Synthesis and Pharmacological Evaluation of the Stereoisomersof 3-Carba Cyclic-Phosphatidic Acid

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 24; pp. 7525 - 7528
• Main Authors: Gupte, Renuka, Siddam, Anjaih, Lu, Yan, Li, Wei, Fujiwara, Yuko, Panupinthu, Nattapon, Truc-ChiPham, Baker, Daniel L., Parrill, Abby L., Gotoh, Mari, Murakami-Murofushi, Kimiko, Mills, Gordon B., Tigyi, Gabor, Miller, Duane D.
• Format: Journal Article
• Language: English
• Published: 08-10-2010
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.09.115

Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a 5-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 LPA
5
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 LPA
5
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.