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

doi:10.1016/j.ejmech.2010.06.005

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 journal › Article › peer-review

24 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 language	English (US)
Pages (from-to)	4149-4156
Number of pages	8
Journal	European Journal of Medicinal Chemistry
Volume	45
Issue number	9
DOIs	https://doi.org/10.1016/j.ejmech.2010.06.005
State	Published - Sep 2010

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery
Organic Chemistry

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2010.06.005

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title = "Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs",

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.",

author = "Sharma, {Arun K.} and Sk, {Ugir Hossain} and Gimbor, {Melissa A.} and Hengst, {Jeremy A.} and Xujun Wang and Jong Yun and Shantu Amin",

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T1 - Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs

AU - Sharma, Arun K.

AU - Sk, Ugir Hossain

AU - Gimbor, Melissa A.

AU - Hengst, Jeremy A.

AU - Wang, Xujun

AU - Yun, Jong

AU - Amin, Shantu

PY - 2010/9

Y1 - 2010/9

N2 - 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.

AB - 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

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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