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Aromatic phosphonates inhibit the lysophospholipase D activity of autotaxin.

Abstract：

:Autotaxin (ATX) is an attractive target for the anticancer therapeutics that inhibits angiogenesis, invasion and migration. ATX is an extracellular lysophospholipase D that hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid. The aromatic phosphonate S32826 was the first described nanomolar inhibitor of ATX. However, the tridecylamide substituent on aromatic ring contributed to its poor solubility and bioavailability, severely limiting its utility in vivo. cLogP calculations revealed that the lipophilicity of S32826 could be lowered by shortening its hydrophobic chain and by introducing substituents alpha to the phosphonate. Herein, we describe the synthesis of a small set of α-substituted phosphonate analogs of S32826, and we show that shortening the chain and adding α-halo or α-hydroxy substituents increased solubility; however, ATX inhibition was reduced by most substitutions. An optimal compound was identified for examination of biological effects of ATX inhibition in vivo.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Jiang G,Madan D,Prestwich GD

doi

10.1016/j.bmcl.2011.03.068

subject

Has Abstract

pub_date

2011-09-01 00:00:00

pages

5098-101

issue

17

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)00387-8

journal_volume

21

pub_type

杂志文章

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