Design, synthesis and biological evaluation of phosphonate analogs as autotaxin (ATX, NPP2) inhibitors

Autotaxin (ATX, NPP2) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known 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. In this thesis we have synthesized a series of alpha- and beta-substituted phosphonate analogs of LPA. ATX inhibitory activity was determined for these compounds. Most of the compounds could block ATX activity at the concentration of 100 muM. Two beta-hydroxy phosphonates, which originated from protected L-tyrosine, were identified as the lead compounds. They were able to inhibit ATX activity at lower concentrations. The stereochemistry of the original tyrosine and the beta-hydroxy functional group and the nature of the pyridyl moiety proved to be important to the activity. Further SAR study was attempted based on the lead compounds. The stereochemistry of the diastereomeric beta-hydroxyphosphonates was also studied.