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

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• 作者：Arun K. Sharma ; Ugir Hossain Sk ; Melissa A. Gimbor ; Jeremy A. Hengst ; Xujun Wang ; Jong Yun ; Shantu Amin
• 关键词：Sphingosine kinase ; Sphingosine kinase inhibitors ; Aspirin ; Prodrugs
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 2010
• 年：2010
• 卷：45
• 期：9
• 页码：4149-4156
• 全文大小：368 K

文摘

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.