Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid.
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.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Renuka
R
Gupte
Anjaih
A
Siddam
Yan
Y
Lu
Wei
W
Li
Yuko
Y
Fujiwara
Nattapon
N
Panupinthu
Truc-Chi
TC
Pham
Daniel L
DL
Baker
Abby L
AL
Parrill
Mari
M
Gotoh
Kimiko
K
Murakami-Murofushi
Susumu
S
Kobayashi
Gordon B
GB
Mills
Gabor
G
Tigyi
Duane D
DD
Miller
D000818:Animals; D004195:Disease Models, Animal; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008245:Lysophospholipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010712:Phosphatidic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000378:metabolism; D013237:Stereoisomerism; D000099189:Lysophospholipase D
D008245:Lysophospholipase; D009097:Multienzyme Complexes; D010712:Phosphatidic Acids; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C556353:3-carba cyclic-phosphatidic acid