Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors.
Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of beta-keto and beta-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors.
Cui
Peng
P
Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, VA 22904, USA. pc3n@virginia.edu
Tomsig
Jose L
JL
McCalmont
William F
WF
Lee
Sangderk
S
Becker
Christopher J
CJ
Lynch
Kevin R
KR
Macdonald
Timothy L
TL
D006868:Hydrolysis; D007202:Indicators and Reagents; D008246:Lysophospholipids / Q000138:chemical synthesis / Q000737:chemistry; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
D007202:Indicators and Reagents; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D063065:Organophosphonates; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid