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

15 Citations (Scopus)

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

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Bioactivity
Pharmacokinetics
Prodrugs
Half-Life
Neoplasms
Phosphotransferases
Cells
Lipids
Cell Line
sphingosine kinase

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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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.",
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Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs. / Sharma, Arun K.; Sk, Ugir Hossain; Gimbor, Melissa A.; Hengst, Jeremy A.; Wang, Xujun; Yun, Jong; Amin, Shantu.

In: European Journal of Medicinal Chemistry, Vol. 45, No. 9, 01.09.2010, p. 4149-4156.

Research output: Contribution to journalArticle

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AU - Gimbor, Melissa A.

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AU - Amin, Shantu

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