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

✍ Scribed by 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

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 395 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.09.115

✦ Synopsis

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 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.