Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs

Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIS) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines: in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from similar to 7 h in SKI-I to similar to 10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem. (C) 2010 Elsevier Masson SAS. All rights reserved.