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

Arun K. Sharma, Ugir Hossain Sk, Melissa A. Gimbor, Jeremy A. Hengst, Xujun Wang, Jong Yun, Shantu Amin

Research output: Contribution to journalArticle

16 Scopus citations

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 languageEnglish (US)
Pages (from-to)4149-4156
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number9
DOIs
StatePublished - Sep 1 2010

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs'. Together they form a unique fingerprint.

  • Cite this