α- and β-Substituted phosphonate analogs of LPA as autotaxin inhibitors

Abstract

Autotaxin (ATX) is an attractive pharmacological target due to its lysophospholipase D activity which leads to the production of lysophosphatidic acid (LPA). Blockage of ATX produced LPA by small molecules could be a potential anticancer chemotherapy. In our previous study, we have identified the two beta-hydroxy phosphonate analogs of LPA (compounds f17 and f18) as ATX inhibitors. With this work, we investigated alpha- and beta-substituted phosphonate analogs of LPA and evaluated them for ATX inhibitory activity. The stereochemistry of beta-hydroxy phosphonates was also studied.

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

“…Direct targeting of LPA receptors seems to be a less attractive strategy, since LPA acts on multiple receptors that show overlapping activities (2 and 6). Since the initial finding that ATX is subject to product inhibition by LPA and sphingosine 1-phosphate (S1P) (22), various synthetic phospho-and phosphonate lipids have been explored as ATX inhibitors (23)(24)(25)(26). However, such lipid inhibitors have the inherent danger of inadvertently activating downstream LPA/S1P receptors, thereby inducing the opposite of the intended effect.…”

Stereoselective synthesis of GABOB, carnitine and statine phosphonates analogues

“…77 Furthermore, the c-amino-b-hydroxyphosphonic acids have been also used as potent sphingosine-1-phosphate (S1P) receptors, 78 and as polysaccharide fragments. 79 The principal synthetic strategies used for the synthesis of phosphostatine and derivatives can be classified into C-P bond formation via oxiranes ring opening derived from amino acids, with dialkylphosphites (1), aldol type reaction of a-aminoaldehydes with dialkyl methylphosphonates (2), diastereoselective reduction of b-ketophosphonates (3), and by catalytic asymmetric aminohydroxylation of b,c-unsaturated phosphonates (4), (Scheme 28).…”

Autotaxin – A Target for the Treatment of Drug-Resistant Ovarian Cancer?

“…In this section we have concentrated on recent reports of small molecule inhibitors of autotaxin. Cui and Macdonald have developed a series of tyrosine-derived -hydroxyphosphonates as analogues of LPA that display activity as inhibitors of autotaxin (Cui et al 2007;Cui et al 2008). The synthesis of this series of compounds is highlighted in Figure 3.…”

“…The sodium borohydride reduction step gave rise to a mixture of two diasteroisomeric products that were separated and isolated by column chromatography. In the initial publications (Cui et al 2007;Cui et al 2008) the relative stereochemistry at the new chiral centre had not been determined, but later work from this group on a more advanced series of inhibitors gave insight to the relationship between stereochemistry and activity in the lead compounds (East et al 2010). From an initial series of targets prepared (R 1 = C 15 H 31 , variation of R 2 ), the most active compound to be identified was compound 1a, derived from S-tyrosine and later confirmed to have the relative stereochemistry shown (Fig.…”