Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators.

Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators.

Sphingosine kinase 1 (SK1) is over-expressed in many cancers where it provides a selective growth and survival advantage to these cells. SK1 is thus a target for anti-cancer agents that can promote apoptosis of cancer cells. In previous work, we synthesized a novel allosteric SK1 inhibitor, (S)-FTY720 vinylphosphonate. We now report a more expeditious route to this inhibitor which features B-alkyl Suzuki coupling as a key step and show that replacement of the amino group in (S)-FTY720 vinylphosphonate with an azido group converts the vinylphosphonate from an allosteric inhibitor to an activator of SK1 at low micromolar concentrations. Our results demonstrate the feasibility of using the (S)-FTY720 vinylphosphonate scaffold to define structure-activity relationships in the allosteric site of SK1.

鞘氨醇激酶1（SK1）在许多癌症中过度表达，为这些细胞提供了选择性的生长和生存优势。因此，SK1是抗癌药物的一个靶点，抗癌药物可促进癌细胞凋亡。在先前的工作中，我们合成了一种新型的变构SK1抑制剂，(S)-FTY720乙烯基膦酸酯。我们现在报道了一种合成这种抑制剂的更快捷的路线，该路线以B - 烷基铃木耦合为关键步骤，并且表明用叠氮基取代(S)-FTY720乙烯基膦酸酯中的氨基，可使乙烯基膦酸酯在低微摩尔浓度下从变构抑制剂转变为SK1的激活剂。我们的结果证明了使用(S)-FTY720乙烯基膦酸酯支架来确定SK1变构位点的构效关系的可行性。