Abstract
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 ∼7 h in SKI-I 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.
Original language | English (US) |
---|---|
Pages (from-to) | 4149-4156 |
Number of pages | 8 |
Journal | European Journal of Medicinal Chemistry |
Volume | 45 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2010 |
All Science Journal Classification (ASJC) codes
- Pharmacology
- Drug Discovery
- Organic Chemistry