Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors.

Abstract

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.

• Authors: Peng Cui, Jose L Tomsig, William F McCalmont, Sangderk Lee, Christopher J Becker, Kevin R Lynch, Timothy L Macdonald
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 17 Issue 6 Pg. 1634-40 (Mar 15 2007) ISSN: 0960-894X [Print] England
• PMID: 17257836 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Indicators and Reagents
• Lysophospholipids
• Multienzyme Complexes
• Organophosphonates
• Phosphoric Diester Hydrolases
• Phosphodiesterase I
• alkylglycerophosphoethanolamine phosphodiesterase
• Pyrophosphatases
• lysophosphatidic acid

Topics

• Hydrolysis
• Indicators and Reagents
• Lysophospholipids (chemical synthesis, chemistry)
• Multienzyme Complexes (antagonists & inhibitors)
• Organophosphonates (chemical synthesis, pharmacology)
• Phosphodiesterase I (antagonists & inhibitors)
• Phosphoric Diester Hydrolases
• Pyrophosphatases (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship